JP6779867B2 - Pyrimidine compounds and how to use them - Google Patents

Description

Description of Federally Funded Research The present invention was made with government support at Grant No. STTR 1R41G042205-1 given by the National Institutes of Health. The United States Government has certain rights to the invention.

In general, the invention relates to a pyrimidine small molecule inhibitor of heat shock protein 90 (Hsp90) and a pharmaceutical composition thereof. The present invention further relates to methods of treating subjects with neurodegenerative diseases.

The Hsp90 protein is involved in stabilizing protein structure and maintaining the function and ATPase activity of many cell signaling proteins. Hsp90 activity is also required for proper folding, stabilization, activation, and localization of neoplastic proteins involved in tumor progression. The N-terminal ATP binding domain is involved in the ATPase activity of this protein, and this adenine nucleotide binding pocket is highly conserved in all Hsp90 proteins, from bacteria to mammals, but is absent in other chaperones.

Since many Hsp90 client proteins themselves have been identified as targets for cancer treatment, Hsp90 proteins have emerged as important targets in cancer treatment. Exemplary Hsp90 client proteins associated with cancer include HER2 (breast breast cancer), Raf-1 / mutant BRAF (melanoma), mutant EGFR (non-small cell lung cancer, glioblastoma), c-Kit. (GIST), c-Met (stomach, lung, glioblastoma), HIF-1α (kidney cancer), Zap70 (chronic lymphocytic leukemia), Bcr-Abl (chronic myelogenous leukemia), MBcr-Abl (chronic) Myelogenous leukemia), Flt-3 (acute myelogenous leukemia), IGF-1R / Akt (myelogenous tumor), NMP-ALK (lymphoma), and Akt (small cell lung cancer). Overexpression of a mutant Hsp90 client or amplification of that client, such as HER2, leads to increased dependence of tumor cells on Hsp90 chaperone function. Therefore, Hsp90 is a viable target for treating various types of tumors.

Increased levels of Hsp90 are also involved in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and tauopathy. Tauopathy is a neurodegenerative disease characterized by abnormalities in tau protein that result in hyperphosphorylation and accumulation of aggregated tau protein. It has been suggested that hyperphosphorylated tau in Alzheimer's disease is a pathogenic process caused by aberrant activation of kinases, especially cdk5 and GSK β3. Studies have shown that Hsp90 stabilizes p35, an activator of cdk5, leading to increased taurine oxidation. It has also been shown that inhibition of Hsp90 activates heat shock factor 1 (HSF1) and thus increases expression of Hsp70. Increased expression of Hsp70 promotes tau solubility and binding to microtubules, inhibits Aβ peptide aggregation, and enhances Aβ peptide degradation.

Hsp90 has also emerged as a target for treating viral, fungal, and bacterial infections. For example, an Hsp90 inhibitor (gerdanamycin) has been shown to slow the growth of influenza virus in cell cultures. Other viruses that depend on the Hsp90-dependent process include those belonging to the following families: Herpesviridae (eg, simple herpesvirus type 1, simple herpesvirus type 2, herpes herpesvirus type 5, Kaposi sarcoma-related herpesvirus, varicella herpes virus, or Epstein bar virus), Polyomaviridae (eg, SV40), Poxviridae (eg, vaccinia virus), Leoviridae (Eg, Rotavirus), Birnaviridae (eg, infectious Fabricius cyst virus), picornaviridae (eg, poliovirus, rhinovirus, or coxsackie virus), flaviviridae ) (For example, hepatitis C virus or dengue virus), arenaviridae (for example, lymphocytic choriomyelitis virus), Hepeviridae (for example, hepatitis E virus), Rhabdoviridae ) (For example, bullous stomatitis virus), Paramixyviridae (for example, human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus), Bunyaviridae ) (Eg, Lacrossvirus), Orthomoxyviridae (eg, influenza A virus), Firoviridae (eg, Ebolavirus), Retroviridae (eg, HTLV1 or HIV1) , And Hepadnaviridae (eg, hepatitis B virus). Hsp90 inhibitors are also used in the treatment of fungal infections, such as Candida albicans, Aspergillus fumigates, or Pneumocystis jirovec in vivo. In addition, Hsp90 inhibitors are also useful in the treatment of bacterial infections such as acid-fast bacilli, anthrax, or bacterial pneumonia.

In view of the above, inhibitors of Hsp90 are beneficial therapeutics for the treatment of diseases such as cancer, neurodegenerative diseases, and infectious diseases.

（式中、
Ｚ¹が、−ＯＲ⁷、−Ｎ（Ｒ¹⁰）Ｒ⁷、−ＳＲ⁷、または−Ｃ（Ｒ¹⁰）（Ｒ¹¹）Ｒ⁷であり；
Ｚ²が、−Ｎ＝または−Ｃ（Ｒ³）＝であり；
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキル（例えば、Ｃ_1〜3アシル）であり；
Ｒ³が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるアミノであり、かつＲ⁴が、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄からなる群から選択される１〜３個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
各Ｒ⁵およびＲ⁶が、独立して、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル（ａｌｋｃｙｃｌｏａｌｋｙｌ）、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル（ａｌｋｈｅｔｅｒｏｃｙｃｌｙｌ）、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員、六員、または七員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｒ¹⁰が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ¹¹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキルであり、またはＲ¹⁰およびＲ¹¹が結合して、＝Ｏまたは＝Ｓを形成し；および
Ｒ^mが、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜4アルキル（例えば、Ｃ_1〜4アシル）、または任意選択的に置換されるＣ_1〜3アルコキシである）
で表される化合物、またはその薬学的に許容できる塩を特徴とする。 In one aspect, the present invention describes the formula (I):

(During the ceremony,
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
Z ² is -N = or -C (R ³ ) =;
Each R ¹ and R ² is a C _1-3 alkyl (eg, C _1-3 acyl) that is independently substituted with H or optionally;
R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkoxy, or C _{6 to 10} aryl optionally substituted, or R ³ and R ⁴ are bonded together with the atoms to which they are bonded, nitrogen, oxygen, and sulfur. 1 to 3 heteroatoms selected from the group consisting of forming a five-membered or six-membered ring is optionally substituted, including optionally, wherein the nitrogen is optionally in R ⁹ Replaced;
Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkcycloalkyl, optionally substituted C _1-3 alkheterocyclyl. ), Or optionally substituted C _1-3 alkaline, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, and nitrogen. Forming optionally substituted five-, six-, or seven-membered rings containing one or two heteroatoms selected from, oxygen, and sulfur;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or optionally substituted C _1-3 alkalil, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ are attached. And = O or = S; and R ^m is H, halogen, cyano, optionally substituted C _1-4 alkyl (eg, C _1-4 acyl), or optionally substituted. C1 to ₃ alkoxy
It is characterized by a compound represented by, or a pharmaceutically acceptable salt thereof.

を有するか、またはその薬学的に許容できる塩である）。 In a particular embodiment of formula (I), R ^m is H (eg, a compound of formula (I) has the following structure:

Or is a pharmaceutically acceptable salt thereof).

In a particular embodiment of formula (I), Z ² is CR ³ , R ¹ and R ² are each H, R ³ is H, and R ⁴ is methyl or halogen (eg, chloro). And if each of R ⁵ and R ⁶ is a halogen (eg, chloro), then Z ¹ is not methoxy.

In a particular embodiment of formula (I), Z ² is CR ³ , R ³ is H, R ⁴ is methyl or halogen (eg, chloro), and each of R ⁵ and R ⁶ is If it is a halogen (eg, chloro), Z ² is not an unsubstituted C _1-3 alkoxy.

In a particular embodiment of formula (I), Z ² is N, R ³ is H, R ⁴ is optionally substituted C _1-6 thioalkoxy, R ⁵ and R ⁶ If each of these is a halogen (eg, chloro), then Z ¹ is not cyanomethoxy or aminomethoxy.

In another embodiment of formula (I), Z ² is N, R ³ is H, each of R ⁵ and R ⁶ is a halogen (eg, chloro), and R ⁴ is a substitution C _{1 to. If 6} thioalkoxy, Z ¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), where Z ² is N, R ³ is H, and R ⁴ is optionally substituted C _1-6 thioalkoxy, then Z ¹ is cyano. Not methoxy or aminomethoxy.

In a particular embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy, then Z ¹ is not cyanomethoxy or aminomethoxy. ..

In a further embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy, then Z ¹ is not substituted C ₁ alkoxy.

In a particular embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy, then Z ¹ is -OR ⁷ , -N. (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted with methyl, dialkylaminoethyl, C _{1 to 3} Alkoxyalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaline, or atoms to which R ⁷ and R ⁸ are bonded, respectively. Together, they form a optionally substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In another embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). If Z ¹ is not 2-amino-2oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy.

In yet another embodiment of formula (I), if Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is 2-amino-2. Not oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy.

In yet another embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). If so, Z ¹ is -OR ⁷ , -N (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is dimethylaminoethyl. a C _{1 to 3} alkheterocyclyl are optionally substituted by C _{1 to 3} alk cycloalkyl or optionally substituted, or R ⁷ and R ^8, together with the atom to which each is bound , Bond to form an arbitrarily substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a further embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). , Z ¹ are -OR ⁷ , -N (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally replaced. Is C _1-3 arccycloalkyl, or optionally substituted C _1-3 archeterocyclyl, or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, and nitrogen. , Oxygen, and sulfur to form a optionally substituted five- or six-membered ring containing one or two heteroatoms optionally selected.

In a particular embodiment of formula (I), if Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is -OR ⁷ , -N. (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted C _1-3 arccycloalkyl, or One of C _1-3 archeterocyclyls optionally substituted, or R ⁷ and R ⁸ bonded together with the atom to which each is bonded, selected from nitrogen, oxygen, and sulfur. Alternatively, it forms a optionally substituted 5- or 6-membered ring containing two heteroatoms.

で表される基を形成する場合、Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでない。 In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Equation (IIa):

When forming a group represented by, R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl. , 2-Hydroxyethyl, 2-oxo-propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not a substituted alkyl, an unsubstituted alkyl, or an unsubstituted C ₂ alkhetaroaryl.

In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Therefore, when forming a group represented by the formula (IIa), R ⁷ is not an alkyl or unsubstituted C ₂ arc heteroaryl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not a substituted alkyl, an unsubstituted alkyl, or an unsubstituted C ₂ archeterocyclyl.

In another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not an alkyl or a C ₂ arc heterocyclyl.

In yet another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are. When bonded to form a group represented by formula (IIa), R ⁷ and R ⁸ are bonded together with the atom to which they are bonded and selected from nitrogen, oxygen, and sulfur1 It forms a five- or six-membered ring that is optionally substituted and optionally contains one or two heteroatoms.

In yet another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ² is CR ³ , and R ³ and R ⁴ are combined to form formula (IIa). When forming the represented group, Z is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

In certain embodiments of formula (I), each R ⁵ and R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. When forming the group represented by (IIa), R ⁷ is not methyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIa), R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1). -Il) ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl- Not isooxazole-3-yl-methyl, 4-methyl-imidazole-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by formula (IIa), R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheteroaryl, or a substituted alkheteroaryl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIa), R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheterocyclyl, or a substituted alkheterocyclyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −. If Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁹ is ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobuta. Not dienylaminocarbonyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −. If Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁹ is H or -C (O) -N (H). )-(Linear C _1-3 alkyl).

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is halo, Z ² is CR ³ , and R ³ and R ⁴ are combined to represent a group of formula (IIa). If Z is -OR ⁷ , R ⁷ is not methyl or 2-chloroethyl, and R ⁹ is H or -C (O) -N (H)-(linear C _{1 to 3} alkyl).

In certain embodiments of formula (I), R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. When forming a group represented by the formula (IIa), R ⁷ is not methyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not methyl.

で表される基を形成する場合、Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IIb) or (IIc)

When forming a group represented by, R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIb) or (IIc), R ⁷ and R ⁸ are bonded together with the atom to which each is bonded and selected from nitrogen, oxygen, and sulfur1 It forms a five- or six-membered ring that is optionally substituted and optionally contains one or two heteroatoms.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ² is CR ³ , and R ³ and R ⁴ are combined to form formula (IIb) or (IIc). When forming the represented group, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

で表される基を形成する場合、Ｒ⁶がブロモでない。 In certain embodiments of formula (I), R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Equation (IIIa)

When forming a group represented by, R ⁶ is not bromo.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIIa), R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2- (N, N-dimethylamino) ethyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIIa), R ⁸ is not H.

In certain embodiments of formula (I), where Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIIa), then R ⁵ and R ⁶ respectively. Chloro, R ⁷ is methyl, R ⁸ is H, or R ⁷ and R ⁸ are bonded together with the atoms to which they are bound and selected from nitrogen, oxygen, and sulfur. It forms a five- or six-membered ring that is optionally substituted and optionally contains one or two heteroatoms.

で表される基を形成する場合、Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In another embodiment of formula (I), R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, equation (IIIb):

When forming a group represented by, neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIIb), each R ¹ and R ² is H.

で表される基を形成する場合、Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVa):

When forming the group represented by, R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidine-4-yl, 2- (1-). Not methyl-pyrrolidin-2-yl) ethyl or 3- (N, N-diethylamino) propyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVa), R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaline.

In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVb):
c (IVb)
When forming a group represented by, R ⁷ is not 2-methoxyethyl or benzyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVb), R ⁷ is not a substituted alkyl or alkaline.

で表される基を形成する場合、Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVc):

When forming a group represented by, R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVc), R ⁷ is not a substituted alkyl.

で表される基を形成する場合、Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでない。 In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. Equation (IVd):

When forming a group represented by, R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVd), R ⁷ is not a substituted alkyl or alkheterocyclyl.

で表される基を形成する場合、Ｒ⁷がベンジルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVe) or (IVf):

When forming a group represented by, R ⁷ is not benzyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVe) or (IVf), R ⁷ is not alkaline.

で表される基を形成する場合、Ｒ⁷がメチルでない。 In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, the formula (IVg), (IVh), (IVi), (IVj), or (IVk):

When forming a group represented by, R ⁷ is not methyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IVg), (IVh), (IVi), (IVj), or (IVk), R ⁷ is not alkyl.

In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. When forming a group represented by the formula (IVg), (IVh), (IVi), (IVj), or (IVk), R ⁷ and R ⁸ are combined with the atom to which each is bonded. They combine to form an optionally substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a particular embodiment of formula (I), if R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and Z ² is CR ³ , then R ³ and R ⁴ are. , (IVg), (IVh), (IVi), (IVj), or (IVk) do not bind to form a group.

In a particular embodiment of formula (I), if R ⁶ is methyl, then each R ¹ and R ² is H.

In a particular embodiment of formula (I), if R ³ is H and each R ⁵ and R ⁶ is chloro, then R ⁷ is not methyl.

（式中、
Ｚ¹が、−ＯＲ⁷、−Ｎ（Ｒ¹⁰）Ｒ⁷、−ＳＲ⁷、または−Ｃ（Ｒ¹⁰）（Ｒ¹¹）Ｒ⁷であり；
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、任意選択的に置換されるＣ_1〜3アルキル、または任意選択的に置換されるＣ_1〜3アルコキシであり、かつＲ⁴が、ハロゲン、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルキル、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄からなる群から選択される１〜３個のヘテロ原子を任意選択的に含む任意選択的に置換される五員、六員、または七員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
各Ｒ⁵およびＲ⁶が、独立して、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員、六員、または七員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｒ¹⁰が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル（例えば、任意選択的に置換されるＣ_1〜3アシル）、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ¹¹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキルであり、またはＲ¹⁰およびＲ¹¹が結合して、＝Ｏまたは＝Ｓを形成する）
で表されるか、またはその薬学的に許容できる塩である。 In certain embodiments, the compounds are of formula (Ia) :.

(During the ceremony,
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted. C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkyl, or optionally substituted 1-3 heteroatoms selected from the group consisting of C _6-10 aryl, or R ³ and R ⁴ bonded together with the atoms to which they are bonded, consisting of nitrogen, oxygen, and sulfur. To form a optionally substituted 5-membered, 6-membered, or 7-membered ring, where nitrogen is optionally substituted with R ⁹ ;
Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 arccycloalkyl, optionally substituted C _1-3 archeterocyclyl, or optionally substituted Are C _1-3 alkalines substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, from nitrogen, oxygen, and sulfur. Forming optionally substituted five-, six-, or seven-membered rings containing one or two selected heteroatoms;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
R ¹⁰ is H, C _1-3 alkyl optionally substituted (eg, C _1-3 acyls optionally substituted), C _3-8 cycloalkyl optionally substituted, optional Selectively substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-3 alk cycloalkyl, C _{1 to 3} alkheterocyclyl, or optionally C _{1 to 3} alkaryl substituted, are optionally substituted, and C R ¹¹ is, for H, is optionally substituted _{1 to 3} alkyl, or R ¹⁰ and R ¹¹ combine to form = O or = S)
A salt represented by or pharmaceutically acceptable thereof.

In other embodiments, Z if R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro. ¹ is not methoxy.

In yet another embodiment, if R ³ is H and R ⁴ is a halogen (eg, chloro), then Z ¹ is 2-amino-2oxoethoxy, 2- (N, N-diethylamino) ethoxy. , Methoxy, or benzyloxy.

In yet another embodiment, if R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is -OR ⁷ , -N. (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted with dimethylaminoethyl, C _1-3 atoms. Cycloalkyl, or C _1-3 archeterocyclyls optionally substituted, or R ⁷ and R ⁸ bonded together with the atoms to which they are bonded, selected from nitrogen, oxygen, and sulfur. It forms a optionally substituted five- or six-membered ring containing one or two heteroatoms that are optionally substituted.

In a further embodiment, if R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is -OR ⁷ , -N (R). ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted C _1-3 arccycloalkyl, or optionally. ₁ or 2 of C _1-3 archeterocyclyls to be substituted, or R ⁷ and R ⁸ bonded together with the atom to which each is bonded, selected from nitrogen, oxygen, and sulfur. It forms a five- or six-membered ring that is optionally substituted with an optional heteroatom.

In certain embodiments, if R ³ is H and R ⁴ is halogen (eg, chloro), then Z ¹ is -OR ⁷ , -N (R ⁷ ) R ¹⁰ , -SR ⁷ , or- C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted C _1-3 alkcycloalkyl, or optionally substituted C _1-3 alkheterocyclyl. Or, R ⁷ and R ⁸ optionally bond together with the atom to which they are bonded and optionally contain one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring that is selectively substituted.

で表される基を形成する場合、Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIa):

When forming a group represented by, R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl. , 2-Hydroxyethyl, 2-oxo-propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by formula (IIa). When formed, R ⁷ is not a substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ archeteroaryl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by formula (IIa). If so, R ⁷ is not an alkyl or unsubstituted C ₂ arc heteroaryl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by formula (IIa). When formed, R ⁷ is not a substituted alkyl, unsubstituted alkyl, or unsubstituted C ₂ archeterocyclyl.

In other embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by formula (IIa). When formed, R ⁷ is not alkyl or C ₂ arc heterocyclyl.

In yet another embodiment, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by the formula (IIa). When forming, R ⁷ and R ⁸ optionally contain one or two heteroatoms selected from nitrogen, oxygen, and sulfur, together with the atoms to which they are bonded. Form a five- or six-membered ring that is optionally substituted.

In yet another embodiment, if R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group represented by formula (IIa), then Z is -OR. ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

In certain embodiments, where each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group represented by formula (IIa). R ⁷ is not methyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa). , R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1, 3-Dimethyl-1H-1,2,4-Triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl- Not imidazole-5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In another embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa). , R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheteroaryl, or a substituted alkheteroaryl.

In another embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa). , R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheterocyclyl, or a substituted alkheterocyclyl.

In certain embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ When and R ⁴ combine to form a group represented by formula (IIa), R ⁹ is not an ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ And R ⁴ combine to form a group represented by formula (IIa), where R ⁹ is H or -C (O) -N (H)-(linear C _1-3 alkyl). is there.

In a particular embodiment, where each R ⁵ and R ⁶ is halo and R ³ and R ⁴ combine to form a group represented by formula (IIa), then Z is −OR ⁷ and R ⁷ is not methyl or 2-chloroethyl, and R ⁹ is H or -C (O) -N (H)-(linear C _1-3 alkyl).

In certain embodiments, R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form the group represented by formula (IIa). If so, R ⁷ is not methyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by formula (IIa). If formed, R ⁷ is not methyl.

で表される基を形成する場合、Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IIb) or (IIc).

When forming a group represented by, R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl.

In other embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are attached to be a group represented by formula (IIb) or (IIc). When forming, R ⁷ and R ⁸ optionally contain one or two heteroatoms selected from nitrogen, oxygen, and sulfur, together with the atoms to which they are bonded. Form a five- or six-membered ring that is optionally substituted.

In certain embodiments, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIb) or (IIc), then Z ¹ is − It is OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

で表される基を形成する場合、Ｒ⁶がブロモでない。 In certain embodiments, R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IIIa).

When forming a group represented by, R ⁶ is not bromo.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIIa). , R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2- (N, N-dimethylamino) ethyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ combine to form a group represented by formula (IIIa). , R ⁸ is not H.

In certain embodiments, when R ³ and R ⁴ combine to form a group represented by formula (IIIa), each R ⁵ and R ⁶ is chloro and R ⁷ is methyl and R ⁸ Is H, or R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally selecting one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring that is optionally substituted, including.

で表される基を形成する場合、Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In other embodiments, R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIIb) :.

When forming a group represented by, neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are attached to form a group represented by formula (IIIb). When formed, each R ¹ and R ² is H.

で表される基を形成する場合、Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでない。 In certain embodiments, R ⁵ and R ⁶ are chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IVa):

When forming the group represented by, R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidine-4-yl, 2- (1-). Not methyl-pyrrolidin-2-yl) ethyl or 3- (N, N-diethylamino) propyl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ combine to form a group represented by formula (IVa). , R ⁷ is not substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaline.

で表される基を形成する場合、Ｒ⁷が、２−メトキシエチルまたはベンジルでない。 In certain embodiments, R ⁵ and R ⁶ are chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IVb):

When forming a group represented by, R ⁷ is not 2-methoxyethyl or benzyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IVb). , R ⁷ is not substituted alkyl or alkaline.

で表される基を形成する場合、Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでない。 In certain embodiments, R ⁵ and R ⁶ are chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IVc):

When forming a group represented by, R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl.

In other embodiments, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ combine to form a group represented by formula (IVc). , R ⁷ is not a substituted alkyl.

で表される基を形成する場合、Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでない。 In a particular embodiment, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by, R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ combine to form a group represented by formula (IVd). , R ⁷ is not a substituted alkyl or alkheterocyclyl.

で表される基を形成する場合、Ｒ⁷がベンジルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by, R ⁷ is not benzyl.

In other embodiments, each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to represent a group of formula (IVe) or (IVf). R ⁷ is not alkaline.

で表される基を形成する場合、Ｒ⁷がメチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form formulas (IVg), (IVh), ( IVi), (IVj), or (IVk):

When forming a group represented by, R ⁷ is not methyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to form formulas (IVg), (IVh), ( When forming a group represented by IVi), (IVj), or (IVk), R ⁷ is not alkyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to form formulas (IVg), (IVh), (IVi). ), (IVj), or (IVk), R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded and selected from nitrogen, oxygen, and sulfur. Form an arbitrarily substituted 5- or 6-membered ring containing one or two heteroatoms.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and Z ¹ is −OR ⁷ , then R ³ and R ⁴ are of formulas (IVg), (IVh), (IVi). , (IVj), or (IVk) do not bind to form a group.

In certain embodiments, if R ⁶ is methyl, then each R ¹ and R ² is H.

In certain embodiments, if R ³ is H and each R ⁵ and R ⁶ is chloro, then R ⁷ is not methyl.

In certain embodiments, where R ³ and R ⁴ combine together with the atoms to which they are attached to form a substituted five-membered ring containing one nitrogen, the five-membered ring is substituted with oxo. Not done. In certain embodiments, where R ³ and R ⁴ combine with the atoms to which they are bonded to form a substituted five-membered ring containing one sulfur, the five-membered ring is hydroxy or C. Not replaced with _1-3 alkoxy. In a further embodiment, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur, then R ⁷ and R ⁸ is optionally substituted with an atom to which each is attached, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a member or six-membered ring.

In certain embodiments, R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally selecting one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring that is optionally substituted, including. In other embodiments, R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally selecting one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered saturated ring that is optionally substituted, including. In yet another embodiment, any of R ⁷ and R ⁸ optionally bond together with the atom to which they are bonded and optionally contain one or two heteroatoms selected from nitrogen and oxygen. It forms a five- or six-membered ring that is selectively substituted. In certain embodiments, R ⁷ and R ⁸ combine with the atoms to which they are attached to form a five-membered ring that is optionally substituted.

（式中、
Ｒ¹およびＲ²のそれぞれが、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、任意選択的に置換されるＣ_1〜3アルキル、または任意選択的に置換されるＣ_1〜3アルコキシであり、かつＲ⁴が、ハロゲン、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の硫黄、または１個の酸素を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
Ｒ⁵およびＲ⁶のそれぞれが、独立して、任意選択的に置換されるＣ_1〜3アルキル（例えば、任意選択的に置換されるＣ_1〜3アシル）、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、任意選択的に置換される五員または六員環を形成し；および
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールである）
で表されるか、またはその薬学的に許容できる塩である。 In certain embodiments, the compound is of formula (Ib) :.

(During the ceremony,
Each of R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted. C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkoxy, or optionally substituted C _{6 to 10} aryl, or R ³ and R ⁴ are bonded together with the atoms to which they are bonded, optionally one nitrogen, one sulfur, or one oxygen. Form a five- or six-membered ring that is optionally substituted in, where nitrogen is optionally substituted with R ⁹ ;
Each of R ⁵ and R ⁶ is independently and optionally substituted C _1-3 alkyl (eg, optionally optionally substituted C _1-3 acyl), optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 arccycloalkyl, optionally substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkalil to be substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atom to which each is bonded and optionally substituted. Forming a five- or six-membered ring; and R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 heteroaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-3 arccycloalkyl, optional C _1-3 archeterocyclyls that are selectively substituted, or C _1-3 alkalines that are optionally substituted)
A salt represented by or pharmaceutically acceptable thereof.

In other embodiments, if R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro, then R ⁷ is not methyl.

In yet another embodiment, where R ³ is H and R ⁴ is a halogen (eg, chloro), then R ⁷ is 2-amino-2oxoethyl, 2- (N, N-diethylamino) ethyl, Not methyl or benzyl.

In yet another embodiment, if R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro), then R ⁷ is dimethylaminoethyl, optionally. to C _{1 to 3} alkcycloalkyl be substituted or a C _{1 to 3} alkheterocyclyl are optionally substituted, or R ⁷ and R ^8, together with the atoms to which each is bonded, bound To form a optionally substituted 5- or 6-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a further embodiment, if R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro), then R ⁷ is optionally substituted C. _1-3 alkcycloalkyls, or C _1-3 alkheterocyclyls optionally substituted, or R ⁷ and R ⁸ bonded together with the atoms to which they are bonded, nitrogen, oxygen, And optionally form a optionally substituted five- or six-membered ring containing one or two heteroatoms selected from sulfur.

In certain embodiments, where R ³ is H and R ⁴ is halogen (eg, chloro), R ⁷ is optionally substituted C _1-3 arccycloalkyl, or optionally. C _1-3 archeterocyclyls substituted with, or one or two R ⁷ and R ⁸ bonded together with the atom to which they are bonded, selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring that is optionally substituted with the heteroatom of.

で表される基を形成する場合、Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）−エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are bound to formula (IIa):

When forming a group represented by, R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl. , 2-Hydroxyethyl, 2-oxo-propyl, 2- (N, N-dimethylamino) -ethyl, difluoromethyl, or 2- (t-butylamino) ethyl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is substituted. Not alkyl, unsubstituted alkyl, or unsubstituted C ₂ archeteroaryl.

In other embodiments, where R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is alkyl. Or it is not a C ₂ arc heteroaryl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is substituted. Not alkyl, unsubstituted alkyl, or unsubstituted C ₂ archeterocyclyl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ combine to form a group of formula (IIa), then R ⁷ is alkyl or Not C ₂ arc heterocyclyl.

In yet another embodiment, if R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are combined to form a group represented by formula (IIa), then R ⁷ and R Arbitrary selection in which ⁸ bonds together with the atom to which each is bonded and contains one oxygen atom and optionally another heteroatom selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring to be replaced.

In yet another embodiment, if R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are combined to form a group represented by formula (IIa), then R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

In certain embodiments, if each R ⁵ and R ⁶ is bromo and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is not methyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is methyl, 2-. (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2 , 4-Triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isooxazole-3-yl-methyl, 4-methyl-imidazole-5-yl-methyl, or Not 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is an unsubstituted alkyl, Not a substituted alkyl, an unsubstituted alkheteroaryl, or a substituted alkheteroaryl.

In other embodiments, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is an unsubstituted alkyl, Not a substituted alkyl, an unsubstituted alkheterocyclyl, or a substituted alkheterocyclyl.

In certain embodiments, each R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine to form the formula. When forming the group represented by (IIa), R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl.

In other embodiments, each R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine to form the formula. When forming the group represented by (IIa), R ⁹ is H or -C (O) -N (H)-(linear C _1-3 alkyl).

In certain embodiments, where R ⁵ and R ⁶ are halos and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁹ is H or -C. (O) -N (H)-(linear C _1-3 alkyl).

In certain embodiments, if R ⁵ is methoxy, R ⁶ is methyl, and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁷ is not methyl.

In certain embodiments, if R ⁵ is chloro, R ⁶ is ethyl, and R ³ and R ⁴ combine to form a group of formula (IIa), then R ⁷ is not methyl. ..

で表される基を形成する場合、Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to form formula (IIb) or (IIc).

When forming a group represented by, R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIb) or (IIc), then R ⁷ and R Arbitrary selection in which ⁸ bonds together with the atom to which each is bonded and contains one oxygen atom and optionally another heteroatom selected from nitrogen, oxygen, and sulfur. Form a five- or six-membered ring to be replaced.

In certain embodiments, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIb) or (IIc), then R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

で表される基を形成する場合、Ｒ⁶がブロモでない。 In certain embodiments, R ⁷ is methyl, R ⁵ is chloro, and R ³ and R ⁴ are bound to formula (IIIa).

When forming a group represented by, R ⁶ is not bromo.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIIa), then R ⁷ is isopropyl, 3, Not 3,3-trifluoropropyl, or 2- (N, N-dimethylamino) ethyl.

In a particular embodiment, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IIIa), then R ⁸ is not H.

In certain embodiments, when R ³ and R ⁴ combine to form a group represented by formula (IIIa), each R ⁵ and R ⁶ is chloro, R ⁷ is methyl, and R ⁸ Is H, or R ⁷ and R ⁸ are bonded together with the atom to which they are bonded, containing one oxygen atom and another selected from nitrogen, oxygen, and sulfur. It forms a five- or six-membered ring that is optionally substituted with a heteroatom.

で表される基を形成する場合、Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In other embodiments, R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ are bound to formula (IIIb):

When forming a group represented by, neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ combine to form a group represented by formula (IIIb), then R ¹ and R, respectively. ² is H.

で表される基を形成する場合、Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to form formula (IVa):

When forming the group represented by, R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidine-4-yl, 2- (1-). Not methyl-pyrrolidin-2-yl) ethyl or 3- (N, N-diethylamino) propyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVa), then R ⁷ is a substituted alkyl, heterocyclyl. , Archeterocyclyl, or not alkaline.

で表される基を形成する場合、Ｒ⁷が、２−メトキシエチルまたはベンジルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to formulate (IVb):

When forming a group represented by, R ⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVb), then R ⁷ is a substituted alkyl or arca. Not a reel.

で表される基を形成する場合、Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to form Formula (IVc):

When forming a group represented by, R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVc), then R ⁷ is not a substituted alkyl.

で表される基を形成する場合、Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to formulate (IVd):

When forming a group represented by, R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVd), then R ⁷ is a substituted alkyl or arc. Not heterocyclyl.

で表される基を形成する場合、Ｒ⁷がベンジルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by, R ⁷ is not benzyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVe) or (IVf), then R ⁷ is: Not substituted alkyl or alkaline.

で表される基を形成する場合、Ｒ⁷がメチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are bound to formula (IVg), (IVh), (IVi), (IVj), or ( IVk):

When forming a group represented by, R ⁷ is not methyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are bound to formula (IVg), (IVh), (IVi), (IVj), or (IVk). When forming a group represented by), R ⁷ and R ⁸ are bonded together with the atom to which each is bonded, and one or two heteroatoms selected from nitrogen, oxygen, and sulfur. To form a five- or six-membered ring that is optionally substituted.

In certain embodiments, where R ⁵ is chloro and R ⁶ is bromo, then R ³ and R ⁴ are of formula (IVg), (IVh), (IVi), (IVj), or (IVk). Do not bond to form the represented group.

In certain embodiments, where R ⁶ is methoxy, then each R ¹ and R ² is H.

In certain embodiments, if R ³ is H and each R ⁵ and R ⁶ is chloro, then R ⁷ is not methyl.

In certain embodiments of formula (I), (Ia), or (Ib), R ³ is H, halogen, optionally substituted C _1-3 alkyl (eg, optionally substituted C). _{1 to 3} acyls), or C _1-3 alkoxy optionally substituted, and R ⁴ is halogen, optionally substituted C _{1 to 3} alkyl (eg, optionally substituted). C _1-3 acyls), optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkyl, or optionally substituted C _{6 to 10} aryl, or R ³ and R ⁴ are bonded together with the atoms to which they are bonded, optionally one nitrogen, one oxygen, or one sulfur. To form a 5- or 6-membered ring that is optionally substituted, the nitrogen is optionally substituted with R ⁹ .

In a further embodiment of formula (I), (Ia), or (Ib), R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkylcycloalkyl. a C _{1 to 3} alkheterocyclyl or C _{1 to 3} alkaryl being optionally substituted, it is optionally substituted, and R ⁸ is H; or R ⁷ and R ^8, respectively A five- or six-membered ring that is optionally substituted, along with the atom to be attached, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form.

In certain embodiments, bonded R ³ and R ^4, when forming a group of formula (IIb) or (IIc), the carbonyl group of formula (IIb) or (IIc) is a C ⁶ Close to each other. In other embodiments, where R ³ and R ⁴ combine to form a group represented by formula (IIb) or (IIc), the carbonyl group of formula (IIb) or (IIc) is C ⁵ or It is close to C ⁶ .

In a particular embodiment, when R ³ and R ⁴ combine to form a group represented by formula (IIIa), the N atom of the group represented by formula (IIIa) is in close proximity to C ^5. There is. In a particular embodiment, where R ³ and R ⁴ combine to form a group represented by formula (IIIa), the N atom of the group represented by formula (IIIb) is at C ⁵ or C ⁶ . It is in close proximity.

In certain embodiments, when R ³ and R ⁴ combine to form a group represented by formula (IIIb), the N atom of the group represented by formula (IIIb) is close to C ⁶ . .. In other embodiments, when R ³ and R ⁴ combine to form a group represented by formula (IIIb), the N atom of the group represented by formula (IIIb) is at C ⁵ or C ⁶ . It is in close proximity.

In a particular embodiment, where R ³ and R ⁴ combine to form a group represented by any one of formulas (IVa)-(IVk), any of formulas (IVa)-(IVk). The S atom of the group represented by one is close to C ⁶ . In a particular embodiment, where R ³ and R ⁴ combine to form a group represented by any one of the formulas (IVa)-(IVk), any of the formulas (IVa)-(IVk). The S atom of the group represented by one is close to C ⁵ or C ⁶ .

In certain embodiments, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur, then R ⁷ and R ⁸ bonds together with the atoms to which they are bonded to form a five- or six-membered ring that is optionally substituted. In certain embodiments, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur, then R ⁷ And R ⁸ combine with the atoms to which they are bonded to form a five-membered ring that is optionally substituted. In certain embodiments, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur, then R ⁷ And R ⁸ combine to form a −CH ₂ CH ₂ − group.

In other embodiments, R ⁷ and R ⁸ combine together with the atoms to which they are attached to form a five- or six-membered ring.

In certain embodiments, R ⁷ is a C _1-3 alkyl optionally substituted. In other embodiments, R ⁷ is an unsubstituted C _1-3 alkyl, C _1-3 alkylamino-C _1-3 -alkyl (eg, C _1-3 haloalkylamino-C _1-3 -alkyl (eg, eg). C _1-3 fluoroalkylamino-C _1-3 -alkyl)), di- (C _1-3 alkyl) amino-C _1-3 -alkyl (eg, ^RY1 N ( ^RY2 )-(C _1-3 alkyl)) Alkyl) ^-where each of ^RY1 and ^RY2 is independently unsubstituted C _1-3 alkyl or C _1-3 haloalkylamino-C _1-3 -alkyl (eg, C _1-3 alkyl) _{. 3} Fluoroalkylamino-C _1-3 -alkyl), or C _1-3 haloalkyl (eg, C _1-3 fluoroalkyl). In certain embodiments, R ⁷ is an unsubstituted C _1-3 alkyl, C _1-3 alkylamino-C _1-3 -alkyl (eg C _1-3 haloalkylamino-C _1-3 -alkyl, eg C _1-3 fluoroalkylamino-C _1-3 -alkyl), or di -(C _1-3 alkyl) amino-C _1-3 -alkyl (eg, ^RY1 N ( ^RY2 )-(C _1-3 alkyl) ^-where each of ^RY1 and ^RY2 is Independently, unsubstituted C _1-3 alkyl, or C _1-3 haloalkylamino-C _1-3 -alkyl, eg, C _1-3 fluoroalkylamino-C _1-3 -alkyl).

In yet other embodiments, R ⁷ is an optionally substituted C _1-3 alkyl (eg, R ⁷ is methyl), or R ⁷ is − (CH ₂ ) _k −N (R). ²⁴ ) R ²⁵ , where k is 2 or 3 (eg, k is 2), and each of R ²⁴ and R ²⁵ is independently replaced by H or optionally. C _1-3 alkyl (eg, R ²⁴ and R ²⁵ are each independently and optionally substituted C _1-3 alkyl, eg, R ²⁴ and R ²⁵ are independent, respectively. And C _1-3 haloalkyl (eg, C _1-3 fluoroalkyl); or each of R ²⁴ and R ²⁵ is independently unsubstituted C _1-3 alkyl, eg methyl). ..

In other embodiments, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one nitrogen, on the ring. The optional substituent of is not oxo. In certain embodiments, if R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur, on the ring. The optional substituent of is not hydroxyl or C _1-3 alkoxy.

In yet another embodiment, each R ¹ and R ² is H. In certain embodiments, each R ³ and R ⁴ is an independently optionally substituted C _1-3 alkyl or optionally substituted C _1-3 alkoxy; or R ³ and Five or six members in which R ⁴ is optionally substituted with an atom to which each is attached, optionally containing one nitrogen, one sulfur, or one oxygen. A member ring is formed, where nitrogen is optionally substituted with R ⁹ . In certain embodiments, R ³ and R ⁴ combine with the atoms to which they are attached to form a five-membered ring that is optionally substituted. In certain embodiments, R ³ and R ⁴ combine to form −CH ₂ CH ₂ CH ₂₋ . In certain embodiments, R ³ and R ⁴ combine with the atoms to which they are attached to form an optionally substituted five-membered ring containing one nitrogen. In certain embodiments, R ³ and R ⁴ combine to form -N (R ⁹ ) -CH = CH- (eg, R ⁹ is replaced with H or optionally C _1-3. Alkyl, eg, C _1-3 haloalkyl (eg, C _1-3 fluoroalkyl); or R ⁹ is H). In certain embodiments, the N atom is in close proximity to C ⁵ of formula (I). In certain embodiments, R ³ and R ⁴ combine with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur. In yet another embodiment, R ³ and R ⁴ combine to form −C (R ^13A ) = C (R ^13B ) −S−, where R ^13A is H and R ^13B is. H or C _1-3 alkyl optionally substituted. In certain embodiments, the S atom is in close proximity to C ⁶ of the compounds of the invention. In certain embodiments, R ¹³ is optionally substituted C _1-3 alkyl, eg, R ^13B is -C (O) -R ^13C , where R ^13C is optionally substituted. C _{1 to 3} alkoxy or amino that is optionally substituted. In other embodiments, R ⁴ is C _1-3 alkyl. In certain embodiments, R ⁴ is methyl, ethyl, or isopropyl. In certain embodiments, R ⁴ is C _1-3 alkoxy (eg, R ⁴ is methoxy). In other embodiments, R ⁴ is an optionally substituted C _1-6 thioalkoxy (eg, R ⁴ is 4-amino-4-oxobutyl). In yet another embodiment, R ⁴ is an optionally substituted amino (eg, R ⁴ is a methyl amino). In yet another embodiment, R ⁴ is a halogen (eg, R ⁴ is a chloro). In certain embodiments, R ³ is hydrogen or C _1-3 alkyl (eg, R ³ is hydrogen, methyl, or ethyl). In a further embodiment, R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is. H or -C (O) -R ^13C , where R ^13C is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted. Amino, or C _2-9 heterocyclyls that are optionally substituted.

In certain embodiments, R ³ and R ⁴ combine to form −X ¹ −X ² −X ³⁻ , where
X ¹ is replaced with -S-, -O-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, -N (R ⁹ )-, -N =, H, or optionally. C _1-3 alkyl;
X ² does not exist, or-(CR ¹⁷ R ¹⁸ ) _n-, -S-, -O-, -N =, -N (R ⁹ )-, -C (R ¹⁹ ) =, = N-, = C (R ²⁰ )-or = C (R ²¹ ) -C (R ²² ) =;
X ³ is optionally replaced with − (CR ¹⁴ R ¹⁵ ) −, −S−, −O−, −N (R ⁹ ) −, = N−, = C (R ²³ ) −, halogen. C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;
Each R ¹⁴ and R ¹⁵ is an independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form = O or = S;
Each R ¹⁷ and R ¹⁸ are independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form = O or = S;
Each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are C _1-3 alkyls that are independently substituted with H, or optionally; and n is 1 or 2. Is.

In certain embodiments, in the absence of X ² , the chain of atoms −X ¹ −X ² −X ³⁻ contains no more than one heteroatom, which is selected from nitrogen, oxygen, and sulfur. ..

In certain embodiments, X ¹ is substituted with − (CR ¹⁴ R ¹⁵ ) −, −C (R ¹⁶ ) =, −N (R ⁹ ) −, −N =, or optionally C _{1 to} It is ₃ alkyl.

In certain embodiments, X ¹ is − (CR ¹⁴ R ¹⁵ ) −. In certain embodiments, each R ¹⁴ and R ¹⁵ is H. In other embodiments, X ¹ is −C (R ¹⁶ ) =. In yet another embodiment, R ¹⁶ is H. In yet another embodiment, X ¹ is −N (R ⁹ ) −. In certain embodiments, R ⁹ is H or a C _1-3 alkyl optionally substituted. In certain embodiments, R ⁹ is hydrogen, methyl, or ethyl. In certain embodiments, X ¹ is −N =. In other embodiments, X ¹ is a C _1-3 alkyl optionally substituted. In yet other embodiments, X ² is absent or-(CH ₂ ) _n- , -N (R ⁹ )-, -C (H) =, = C (R ²⁰ )-, or = C ( H) -C (H) =. In yet another embodiment, X ² is −C (H) =. In a further embodiment, X ² is −N (R ⁹ ) −. In certain embodiments, R ⁹ is H. In certain embodiments, R ⁹ is a C _1-3 alkyl optionally substituted (eg, R ⁹ is -C (O) -N (H) -Et). In certain embodiments, X ² is = C (R ²⁰ ) −. In other embodiments, R ²⁰ is a C _1-3 alkyl optionally substituted. In yet other embodiments, X ² is absent. In yet other embodiments, X ³ is −CH _2- , −S−, = C (H) −, −N (R ⁹ ) −, halogen, optionally substituted C _1-3 alkyl, C _{1 to 3} alkoxy optionally substituted, C _{1 to 6} thioalkoxy optionally substituted, and C _{6 to 10} aryl optionally substituted. In certain embodiments, X ³ is −CH ₂₋ . In certain embodiments, X ³ is −S−. In certain embodiments, X ³ is = C (H) −. In other embodiments, X ³ is −N (R ⁹ ) −. In yet other embodiments, X ³ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6. It is thioalkoxy, or C _6-10 aryl, which is optionally substituted.

In certain embodiments, Z ¹ and R ⁸ combine to form −Z ³ −Y ¹ −Y ²⁻ , where
Z ³ is -O-, -N (R ¹⁰ )-, -N =, -S-, or-(CR ¹¹ R ¹² )-;
Y ¹ is -O-, -N (R ¹⁰ )-, -S-,-(CR ²⁶ R ²⁷ ) _m- , -C (R ²⁰ ) =, = C (R ²⁰ )-, = C (R) ^{21) -C (R 22) =} , C 1~3 alkyl, C _{1 to 3} alkheterocyclyl, C _{1 to 3} alkcycloalkyl which is optionally substituted is optionally substituted is optionally substituted Alkyl, or C _1-3 alkaline alcohol optionally substituted; and Y ² are -O-, -S-, -N (R ¹⁰ )-,-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, = N-, or H; where
Each R ²⁰ , R ²¹ , and R ²² are independently H or optionally substituted C _1-3 alkyl; and each R ²⁶ and R ²⁷ are independently H or optionally. It is a C _1-3 alkyl that is substituted with or that R ²⁶ and R ²⁷ combine to form = O or = S;
m is 1 or 2;
Here, if Y ² is H,
The chain of atoms −Z ³ −Y ¹ −Y ² − contains no more than two heteroatoms, which are selected from nitrogen, oxygen, and sulfur.

In yet another embodiment, R ⁷ and R ⁸ form the group −Y ¹⁻ Y ²⁻ , where:
Y ¹ is − (CR ²⁶ R ²⁷ ) _m −, −C (R ²⁰ ) =, C _1-3 alkyl optionally substituted, C _1-3 arc heterocyclyl optionally substituted, optional Selectively substituted C _1-3 arccycloalkyl, or optionally substituted C _1-3 alkaline;
Y ² is-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, or H; where
Each R ²⁶ and R ²⁷ is a C _1-3 alkyl that is independently substituted with H or optionally; and m is 1 or 2.

In certain embodiments, Z ³ is oxygen. In certain embodiments, Y ¹ is − (CR ²⁶ R ²⁷ ) _m −, −C (R ²⁰ ) =, optionally substituted C _1-3 alkyl, optionally substituted C _{1 to 3} alkheterocyclyl, optionally substituted C _1-3 alkcycloalkyl, or optionally substituted C _1-3 alkaline. In a further embodiment, Y ¹ is − (CR ²⁶ R ²⁷ ) _m − or an optionally substituted C _1-3 alkyl. In other embodiments, Y ¹ is − (CR ²⁶ R ²⁷ ) _m −. In other embodiments, Y ¹ is an optionally substituted C _1-3 alkyl (eg, Y ¹ is methyl). In yet another embodiment, Y ¹ is − (CH ₂ ) _k −N (R ²⁴ ) R ²⁵ , where k is 2 or 3, and each R ²⁴ and R ²⁵ are independent. And H or C _1-3 alkyl optionally substituted. In yet another embodiment, k is 2. In a further embodiment, each R ²⁴ and R ²⁵ is a C _1-3 alkyl that is independently and optionally substituted (eg, each R ²⁴ and R ²⁵ is methyl). In certain embodiments, Y ² is − (CR ²⁶ R ²⁷ ) − or H. In other embodiments, Y ² is − (CR ²⁶ R ²⁷ ) −.

In some embodiments of any aspect, each R ¹ and R ² is H.

、またはその薬学的に許容できる塩で表される構造を有し、式中、全ての置換基が、本明細書において定義されるとおりである。 In a particular embodiment of formula (I) or (Ia), the compounds of the invention are of formula (Va) :.

, Or a structure represented by a pharmaceutically acceptable salt thereof, in which all substituents are as defined herein.

、またはその薬学的に許容できる塩で表される構造を有し、
式中、
Ｘ¹が、−Ｓ−、−Ｏ−、−（ＣＲ¹⁴Ｒ¹⁵）−、−Ｃ（Ｒ¹⁶）＝、−Ｎ（Ｒ⁹）−、−Ｎ＝、−Ｈ、または任意選択的に置換されるＣ_1〜3アルキルであり；
Ｘ²が、存在しないか、−（ＣＲ¹⁷Ｒ¹⁸）_n−、−Ｓ−、−Ｏ−、−Ｎ＝、−Ｎ（Ｒ⁹）−、−Ｃ（Ｒ¹⁹）＝、＝Ｎ−、＝Ｃ（Ｒ²⁰）−、または＝Ｃ（Ｒ²¹）−Ｃ（Ｒ²²）＝であり；
Ｘ³が、−（ＣＲ¹⁴Ｒ¹⁵）−、−Ｓ−、−Ｏ−、−Ｎ（Ｒ⁹）−、＝Ｎ−、＝Ｃ（Ｒ²³）−、ハロゲン、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜6チオアルコキシ、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり；
Ｙ¹が、−（ＣＲ²⁶Ｒ²⁷）_m−、−Ｃ（Ｒ²⁰）＝、＝Ｃ（Ｒ²⁰）−、＝Ｃ（Ｒ²¹）−Ｃ（Ｒ²²）＝、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｙ²が、−Ｏ−、−Ｓ−、−Ｎ（Ｒ¹⁰）−、−（ＣＲ²⁶Ｒ²⁷）−、＝Ｃ（Ｒ²⁰）−、＝Ｎ−、またはＨであり；
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
各Ｒ⁵およびＲ⁶が、独立して、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
各Ｒ¹⁴、Ｒ¹⁵、Ｒ¹⁶、Ｒ¹⁷、Ｒ¹⁷、Ｒ¹⁸、Ｒ²⁰、Ｒ¹⁹、Ｒ²⁰、Ｒ²¹、Ｒ²²、Ｒ²³ _、Ｒ²⁶、およびＲ²⁷が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
ｎが、１または２であり；および
ｍが、１または２である。 In a particular embodiment of formula (I), (Ia), or (Ib), the compounds of the invention are of formula (Vb) :.

, Or a structure represented by its pharmaceutically acceptable salt,
During the ceremony
X ¹ replaces -S-, -O-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, -N (R ⁹ )-, -N =, -H, or optionally _Is C _1-3 alkyl to be;
X ² does not exist, or-(CR ¹⁷ R ¹⁸ ) _n-, -S-, -O-, -N =, -N (R ⁹ )-, -C (R ¹⁹ ) =, = N-, = C (R ²⁰ )-or = C (R ²¹ ) -C (R ²² ) =;
X ³ is optionally replaced with − (CR ¹⁴ R ¹⁵ ) −, −S−, −O−, −N (R ⁹ ) −, = N−, = C (R ²³ ) −, halogen. C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;
Y ¹ is optionally replaced by − (CR ²⁶ R ²⁷ ) _m −, −C (R ²⁰ ) =, = C (R ²⁰ ) −, = C (R ²¹ ) −C (R ²² ) = C _1-3 alkyl, optionally substituted C _1-3 alkheterocyclyl, optionally substituted C _1-3 alkcycloalkyl, or optionally substituted C _1-3 alkaline Is;
Y ² is -O-, -S-, -N (R ¹⁰ )-,-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, = N-, or H;
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
Each R ⁵ and R ⁶ is an independently optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ _, R ²⁶ , and R ²⁷ are independently H. Or a C _1-3 alkyl that is optionally substituted;
n is 1 or 2; and m is 1 or 2.

で表される基を形成する場合、Ｙ¹が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）−エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³ − is of formula (IIa) :.

When forming the group represented by, Y ¹ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl. , 2-Hydroxyethyl, 2-oxo-propyl, 2- (N, N-dimethylamino) -ethyl, difluoromethyl, or 2- (t-butylamino) ethyl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³⁻ forms the group represented by formula (IIa), then Y ¹ is , Not optionally substituted C _1-3 alkyl or optionally substituted C ₂ arc heteroaryl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³ − forms the group represented by formula (IIa), then Y ¹ is , Not optionally substituted C _1-3 alkyl or optionally substituted C ₂ arc heterocyclyl.

In yet another embodiment, if R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³ − forms the group represented by formula (IIa), then Y ² Is not H.

In yet another embodiment, where R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³⁻ form a group represented by formula (IIa), each Y ¹ and Y ² are −CH ₂₋ .

In certain embodiments, if each R ⁵ and R ⁶ is bromo and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIa), then Y ¹ is not methyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIa), then Y ¹ is methyl. 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1 , 2,4-Triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isooxazole-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl , Or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIa), then Y ¹ is unsubstituted. Not alkyl, substituted alkyl, unsubstituted alkheteroaryl, or substituted alkheteroaryl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIa), then Y ¹ is an unsubstituted alkyl. , Substituted alkyl, unsubstituted alkheterocyclyl, or not substituted alkheterocyclyl.

In certain embodiments, each R ⁵ and R ⁶ is chloro, each Y ¹ and Y ² is −CH ₂ −, and −X ¹ −X ² −X ³⁻ is represented by formula (IIa). R ⁹ is not an ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl when forming a group to be.

In other embodiments, each R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and −X ¹ −X ² −X ³ −. , When forming a group represented by the formula (IIa), R ⁹ is H or −C (O) −N (H) − (linear C _1-3 alkyl).

In a particular embodiment, where each R ⁵ and R ⁶ is halo and -X ^1- X ² -X ³ − forms a group represented by formula (IIa), then R ⁹ is H or -C (O) -N (H)-(linear C _1-3 alkyl).

In certain embodiments, where R ⁵ is methoxy, R ⁶ is methyl, and −X ¹ −X ² −X ³ − forms the group represented by formula (IIa), then Y ¹ is methyl. Not.

In a particular embodiment, where R ⁵ is chloro, R ⁶ is ethyl, and −X ¹ −X ² −X ³⁻ forms the group represented by formula (IIa), then Y ¹ is Not methyl.

で表される基を形成する場合、Ｙ¹が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IIb) or (IIc).

When forming a group represented by, Y ¹ is not methyl or 2- (N, N-diethylamino) ethyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIb) or (IIc), then Y ² Is not H.

In a particular embodiment, if each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIb) or (IIc), then each Y ¹ and Y ² are −CH ₂₋ .

で表される基を形成する場合、Ｒ⁶がブロモでない。 In certain embodiments, R ⁷ is methyl, R ⁵ is chloro, and −X ¹ −X ² −X ³ − is of formula (IIIa).

When forming a group represented by, R ⁶ is not bromo.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIIa), then R ⁷ is isopropyl, Not 3,3,3-trifluoropropyl, or 2- (N, N-dimethylamino) ethyl.

In certain embodiments, where −X ¹ −X ² −X ³ − forms a group represented by formula (IIIa), each R ⁵ and R ⁶ is chloro and Y ¹ is methyl. And Y ² is H, or Y ¹ is-(CR ²⁶ R ²⁷ ) _m- , -C (R ²⁰ ) =, = C (R ²⁰ )-, or = C (R ²¹ ) -C (R) ²² ) = and Y ² is -O-, -S-, -N (R ¹⁰ )-,-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, or = N-. ..

In certain embodiments, when −X ¹ −X ² −X ³⁻ forms a group represented by formula (IIIa), each R ⁵ and R ⁶ is chloro, and Y ² is not H.

で表される基を形成する場合、Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In other embodiments, R ⁵ is chloro, R ⁶ is methoxy, and −X ¹ −X ² −X ³ − is of formula (IIIb) :.

When forming a group represented by, neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl.

In certain embodiments, where R ⁵ is chloro, R ⁶ is methoxy, and −X ¹ −X ² −X ³ − forms the group represented by formula (IIIb), each R ¹ And R ² is H.

で表される基を形成する場合、Ｙ¹が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IVa) :.

When forming the group represented by, Y ¹ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidine-4-yl, 2- (1-). Not methyl-pyrrolidin-2-yl) ethyl or 3- (N, N-diethylamino) propyl.

In a particular embodiment, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by the formula (IVa), then Y ¹ is heterocyclyl, Not archeterocyclyl or alkaline.

で表される基を形成する場合、Ｙ¹が、２−メトキシエチルまたはベンジルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IVb) :.

When forming a group represented by, Y ¹ is not 2-methoxyethyl or benzyl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by formula (IVb), then Y ¹ is the substituted alkyl. Or not alkaline.

で表される基を形成する場合、Ｙ¹が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IVc) :.

When forming a group represented by, Y ¹ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl.

In other embodiments, where each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by the formula (IVc), then Y ¹ is the substituted alkyl. Not.

で表される基を形成する場合、Ｙ¹が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでない。 In a particular embodiment, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IVd) :.

When forming a group represented by, Y ¹ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl.

In certain embodiments, where each R ⁵ and R ⁶ is chloro and R ³ and R ⁴ combine to form a group represented by formula (IVd), then Y ¹ is a substituted alkyl or arc. Not heterocyclyl.

で表される基を形成する場合、Ｙ¹がベンジルでない。 In certain embodiments, each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ is of formula (IVe) or (IVf) :.

When forming a group represented by, Y ¹ is not benzyl.

In other embodiments, if each R ⁵ and R ⁶ is chloro and −X ¹ −X ² −X ³⁻ forms a group represented by the formula (IVe) or (IVf), then Y ¹ However, it is not alkaline or substituted alkyl.

で表される基を形成する場合、Ｙ¹がメチルでない。 In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³ − is the formulas (IVg), (IVh), (IVi), (IVj), Or (IVk):

When forming a group represented by, Y ¹ is not methyl.

In certain embodiments, R ⁵ is chloro, R ⁶ is bromo, and −X ¹ −X ² −X ³ − is of formula (IVg), (IVh), (IVi), (IVj), or. When forming a group represented by (IVk), Y ² is not H.

In certain embodiments, where R ⁵ is chloro and R ⁶ is bromo, then R ³ and R ⁴ are of formula (IVg), (IVh), (IVi), (IVj), or (IVk). Do not bond to form the represented group.

In certain embodiments, where R ⁶ is methoxy, then each R ¹ and R ² is H.

In certain embodiments, if X ¹ is H and each R ⁵ and R ⁶ is chloro, then Y ¹ is not methyl.

In certain embodiments, R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _1-3 arc. Cycloalkyl, optionally substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkaline. In another embodiment, _{C. 1 to} R ¹⁰ is, H, optionally substituted by C _{1 to 3} alkyl, C _{1 to 3} alkcycloalkyl which is optionally substituted, which is optionally substituted ₃ archeterocyclyl, or C _1-3 alkaline, which is optionally substituted.

In certain embodiments, X ¹ is − (CR ¹⁴ R ¹⁵ ) −, X ² is −N (R ⁹ ) −, X ³ is − (CR ¹⁴ R ¹⁵ ) −, and R ¹⁴ If each of and R ¹⁵ is H, then R ⁹ is H or -C (O) -N (H) -Et, and each of Y ¹ and Y ² is -CH _2- . In other embodiments, if X ¹ is − (CR ¹⁴ R ¹⁵ ) −, X ² is −N (R ⁹ ) −, and X ³ is − (CR ¹⁴ R ¹⁵ ) −, then R ⁹ is H or -C (O) -N (H) -Et, and each of Y ¹ and Y ² is -CH _2- . In certain embodiments, X ¹ is −N (R ⁹ ) −, X ² is −C (R ¹⁹ ) =, X ³ is = C (R ²³ ) −, and R ¹⁷ , R ¹⁹ , And R ²³ are H, then Y ¹ is − (CR ²⁶ R ²⁷ ) _m − and Y ² is − (CR ²⁶ R ²⁷ ) −. In other embodiments, X ¹ is −N (R ⁹ ) −, X ² is −C (R ¹⁹ ) =, X ³ is = C (R ²³ ) −, and R ⁹ , R. If each of ¹⁹ and R ²³ is H, then each of Y ¹ and Y ² is −CH ₂ −. In certain embodiments, X ¹ is −N (R ⁹ ) −, X ² is −C (R ¹⁹ ) =, X ³ is = C (R ²³ ) −, and R ¹⁹ and R ^23. When each of them is H, Y ¹ is − (CR ²⁶ R ²⁷ ) _m − and Y ² is − (CR ²⁶ R ²⁷ ) −. In certain embodiments, X ¹ is −N (R ⁹ ) −, X ² is −C (R ¹⁹ ) =, X ³ is = C (R ²³ ) −, and Y ² is H. If there is, and each of R ⁵ and R ⁶ is -Cl, then Y ¹ is Me. In a particular embodiment, if X ¹ is −C (R ¹⁶ ) =, X ² is = C (R ²⁰ ) −, and X ³ is −S−, then R ¹⁶ is H. In certain embodiments, if X ¹ is −C (R ¹⁶ ) =, X ² is = C (R ²⁰ ) −, and X ³ is −S−, then Y ¹ is − (CR ²⁶ R). ²⁷ ) _m − and Y ² is − (CR ²⁶ R ²⁷ ) −. In certain embodiments, Y ¹ and Y ² respectively, where X ¹ is −C (R ¹⁶ ) =, X ² is = C (R ²⁰ ) −, and X ³ is −S−. Is −CH ₂ −. In certain embodiments, if X ¹ is −C (R ¹⁶ ) =, X ² is = C (R ²⁰ ) −, and X ³ is −S−, then R ⁵ and R ⁶ are respectively. -Cl. In certain embodiments, if X ¹ is H and R ⁵ and R ⁶ are Cl, then Y ¹ is − (CR ²⁶ R ²⁷ ) _m − and Y ² is − (CR ^26). R ²⁷ )-. In certain embodiments, if X ¹ is H and R ⁵ and R ⁶ are each hal, then Y ¹ is − (CR ²⁶ R ²⁷ ) _m − and Y ² is − (CR ^26). R ²⁷ )-(eg, each of Y ¹ and Y ² is -CH _2- ). In certain embodiments, where X ¹ is H, Y ¹ is − (CR ²⁶ R ²⁷ ) _m − and Y ² is − (CR ²⁶ R ²⁷ ) − (eg, Y ¹ and Y). Each of ² is −CH ₂ −).

In certain embodiments, X ¹ is − (CR ¹⁴ R ¹⁵ ) −, −C (R ¹⁶ ) =, −N (R ⁹ ) −, or C _1-3 alkyl optionally substituted. (For example, -CH _2- , -C (H) =, -N =, C _1-3 alkyl optionally substituted, or -N (R ⁹ )-(eg, R ¹⁷ is H or optional It is a C _1-3 alkyl that is selectively substituted (eg, R ⁹ is H, -Me, or -Et).

In certain embodiments, X ² is absent or-(CH ₂ ) _n- , -N (R ⁹ )-, -C (H) =, = C (R ²⁰ )-, or = C (H). ) -C (H) =. In certain embodiments, X ² is absent or -C (H) =, -N (R ⁹ )-(eg, R ⁹ is H or optionally substituted with C _1-3 alkyl. Is (eg, R ⁹ is C _1-3 haloalkyl, eg, C _1-3 fluoroalkyl), or R ⁹ is -C (O) -N (H) -Et), or = C (R ²⁰ ) −, where R ²⁰ is, for example, a C _1-3 alkyl optionally substituted.

In certain embodiments, X ³ is −CH _2- , −S−, = C (H) −, or an optionally substituted C _1-3 alkyl.

In certain embodiments, each of R ⁵ and R ⁶ is an independently halo, or an optionally substituted C _1-3 alkyl, eg, each of R ⁵ and R ⁶ is halo () For example, each of R ⁵ and R ⁶ is -Cl).

In certain embodiments, R ²⁶ is H. In other embodiments, R ²⁷ is H. In certain embodiments, n is 1. In another embodiment, m is 1. In certain embodiments, Y ¹ is a C _1-3 alkyl optionally substituted. In other embodiments, Y ¹ is unsubstituted C _1-3 alkyl, C _1-3 alkylamino-C _1-3 -alkyl (eg, C _1-3 haloalkylamino-C _1-3 -alkyl, eg, C _1-3 haloalkylamino-C _1-3 -alkyl, eg. C _1-3 fluoroalkylamino-C _1-3 -alkyl), di- (C _1-3 alkyl) amino-C _1-3 -alkyl (eg, ^RY1 N ( ^RY2 )-(C _1-3 alkyl) )-, Where each of ^RY1 and ^RY2 is independently unsubstituted C _1-3 alkyl, or C _1-3 haloalkylamino-C _1-3 -alkyl, eg, C _1-3. Fluoroalkylamino-C _1-3 -alkyl) or C _1-3 haloalkyl (eg, C _1-3 fluoroalkyl). In certain embodiments, Y ¹ is unsubstituted C _1-3 alkyl, C _1-3 alkylamino-C _1-3 -alkyl (eg, C _1-3 haloalkylamino-C _1-3 -alkyl, eg, C _1-3 haloalkylamino-C _1-3 -alkyl, eg. C _1-3 fluoroalkylamino-C _1-3 -alkyl) or di- (C _1-3 alkyl) amino-C _1-3 -alkyl (eg, ^RY1 N ( ^RY2 )-(C _1-3 alkyl) Alkyl)-, where each of ^RY1 and ^RY2 is independently unsubstituted C _1-3 alkyl, or C _1-3 haloalkylamino-C _1-3 -alkyl, eg, C _{1- 3} Fluoroalkylamino-C _1-3 -alkyl).

In certain embodiments, the compounds of the invention are represented by the formulas shown in Table 1 or are pharmaceutically acceptable salts thereof.

で表されるか、またはその薬学的に許容できる塩である。 In certain embodiments, the compounds of the invention have the formula:

A salt represented by or pharmaceutically acceptable thereof.

で表されるか、またはその薬学的に許容できる塩である。 In certain embodiments, the compounds of the invention have the formula:

A salt represented by or pharmaceutically acceptable thereof.

In a further embodiment, the compound is not compound 38 or compound 39.

In a particular embodiment of any of the formulas described herein, R ¹ and R ² are H, R ⁵ is Cl, and R ⁶ is F or Cl, respectively.

In another embodiment of formula (I), (Ia), or (Ib), R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C. _{1 to 3} alkoxy, and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or C _{1 to 6} thioalkoxys that are optionally substituted, or R ³ and R ⁴ are bonded together with the atoms to which they are attached, one nitrogen, one oxygen, or one. It forms a optionally substituted 5- or 6-membered ring containing optionally sulfur, where nitrogen is optionally substituted with R ⁹ .

In yet another embodiment of formula (I), (Ia), or (Ib), R ³ is H, optionally substituted C ₁ alkyl, or optionally substituted C _1-3. Alkoxy and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted Is C _1-6 thioalkoxy substituted with, or R ³ and R ⁴ are bonded together with the atoms to which they are bonded, one nitrogen, one oxygen, or one sulfur. To form a optionally substituted 5- or 6-membered ring containing optionally, where nitrogen is optionally substituted at R ⁹ .

In yet another embodiment of formula (I), (Ia), or (Ib), R ³ is H, optionally substituted C ₁ alkyl, or optionally substituted C _1-3. Alkoxy and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted C _{1 to 6} thioalkoxy substituted with, or with R ³ and R ⁴ attached, the following groups:
-N (R ⁹ ) -CH = CH-, -CH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ CH ₂ CH _2- , and -C (R ^13A ) = C (R ^13B ) -S-
One of which is formed, where N is in close proximity to position 5 and R ⁹ is H or C _1-3 alkyl.

In a particular embodiment of formula (I), Z ² is N and R ⁴ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy. , Amino, which is optionally substituted, or C _1-6 thioalkoxy, which is optionally substituted.

In a particular embodiment of formula (I), Z ² is N and R ⁴ is optionally substituted C _1-3 alkoxy or optionally substituted C _1-6 thioalkoxy. is there.

In other embodiments, X ¹ is -N (R ⁹ )-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, H, or an optionally substituted C ₁ alkyl. .. In yet other embodiments, X ² is absent or − (CR ¹⁷ R ¹⁸ ) _n −, −C (R ¹⁹ ) =, or = C (R ²⁰ ) −. In yet other embodiments, X ³ is − (CR ¹⁴ R ¹⁵ ) −, − S−, = C (R ²³ ) −, halogen, optionally substituted C _1-3 alkyl, optionally. C _{1 to 6} thioalkoxy substituted with, or C _{1 to 3} alkoxy optionally substituted. In certain embodiments, R ⁹ is H or C _1-3 alkyl.

In certain embodiments, the compounds of the invention have a molecular weight of less than about 500 g / mol (eg, less than about 450 g / mol, or less than about 400 g / mol). In other embodiments, the compounds of the invention exceed about 1 × 10 ^-7 cm / sec (eg, greater than about 5 × 10 ^-7 cm / sec, about 1 × 10 ^-6 ) in the MDR1-MDCK assay. Shows (A → B) permeability from apical to basal (greater than cm / sec or about 3 × 10 ^-6 cm / sec). In certain embodiments, the compounds of the invention exhibit a (B → A) / (A → B) ratio of less than about 30 (eg, less than about 10, less than about 5, or less than about 3).

In another aspect, the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier or excipient. To do. In certain embodiments, the composition is oral, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, spinal cord. Formulated for administration intracavitarily, intraperitoneally, or intranasally. Preferably, the composition is formulated for oral administration.

（式中、
Ｚ¹が、−ＯＲ⁷、−Ｎ（Ｒ¹⁰）Ｒ⁷、−ＳＲ⁷、または−Ｃ（Ｒ¹⁰）（Ｒ¹¹）Ｒ⁷であり；
Ｚ²が、−Ｎ＝または−Ｃ（Ｒ³）＝であり；
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるアミノであり、かつＲ⁴が、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の酸素、または１個の硫黄を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
各Ｒ⁵およびＲ⁶が、独立して、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｒ¹⁰が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ¹¹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキルであり、またはＲ¹⁰およびＲ¹¹が結合して、＝Ｏまたは＝Ｓを形成し、および
Ｒ^mが、Ｈ、ハロゲン、任意選択的に置換されるＣ_1〜4アルキル、または任意選択的に置換されるＣ_1〜3アルコキシである）
で表される化合物、またはその薬学的に許容できる塩を哺乳動物に投与する工程を含む。 In yet another aspect, the invention features a method of treating a disease in a mammal (eg, human) caused by the action of heat shock protein 90 (Hsp90). This method is an effective amount of formula (I):

(During the ceremony,
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
Z ² is -N = or -C (R ³ ) =;
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkoxy, or C _{6 to 10} aryl optionally substituted, or R ³ and R ⁴ combined with the atom to which each is attached, one nitrogen, 1 It forms an optionally substituted 5- or 6-membered ring containing an optional oxygen, or 1 sulfur, where nitrogen is optionally substituted with R ⁹ ;
Each R ⁵ and R ⁶ is an independently optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkcycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted Are C _1-3 alkalines substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, from nitrogen, oxygen, and sulfur. Form an arbitrarily substituted five- or six-membered ring containing one or two selected heteroatoms optionally;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or optionally substituted C _1-3 alkalil, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ are attached. = O or = S is formed, and R ^m is H, halogen, optionally substituted C _1-4 alkyl, or optionally substituted C _1-3 alkoxy).
Includes the step of administering to a mammal the compound represented by, or a pharmaceutically acceptable salt thereof.

In a particular embodiment of formula (I), Z ² is CR ³ , R ¹ and R ² are each H, R ³ is H, and R ⁴ is methyl or halogen (eg, chloro). And if each of R ⁵ and R ⁶ is a halogen (eg, chloro), then Z ¹ is not methoxy.

In a particular embodiment of formula (I), Z ² is CR ³ , R ³ is H, R ⁴ is methyl or halogen (eg, chloro), and each of R ⁵ and R ⁶ is If it is a halogen (eg, chloro), Z ² is not an unsubstituted C _1-3 alkoxy.

In a particular embodiment of formula (I), Z ² is N, R ³ is H, R ⁴ is optionally substituted C _1-6 thioalkoxy, and R ⁵ and R. ^If each of ⁶ is a halogen (eg, chloro), then Z ¹ is not cyanomethoxy or aminomethoxy.

In another embodiment of formula (I), Z ² is N, R ³ is H, each of R ⁵ and R ⁶ is a halogen (eg, chloro), and R ⁴ is a substitution C _{1 to. If 6} thioalkoxy, Z ¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), where Z ² is N, R ³ is H, and R ⁴ is optionally substituted C _1-6 thioalkoxy, then Z ¹ is cyano. Not methoxy or aminomethoxy.

In a particular embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy, then Z ¹ is not cyanomethoxy or aminomethoxy. ..

In a further embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is substituted C _1-6 thioalkoxy, then Z ¹ is not substituted C ₁ alkoxy.

In a particular embodiment of formula (I), if Z ² is N, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy, then Z ¹ is -OR ⁷ , -N. (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted with methyl, dialkylaminoethyl, C _{1 to 3} Alkoxyalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted C _1-3 alkaline, or atoms to which R ⁷ and R ⁸ are bonded, respectively. Together, they form a optionally substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In another embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). If Z ¹ is not 2-amino-2oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy.

In yet another embodiment of formula (I), if Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is 2-amino-2. Not oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy.

In yet another embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). If so, Z ¹ is -OR ⁷ , -N (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is dimethylaminoethyl. a C _{1 to 3} alkheterocyclyl are optionally substituted by C _{1 to 3} alk cycloalkyl or optionally substituted, or R ⁷ and R ^8, together with the atom to which each is bound , Bond to form an arbitrarily substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a further embodiment of formula (I), Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen (eg, chloro). , Z ¹ are -OR ⁷ , -N (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally replaced. Is C _1-3 arccycloalkyl, or optionally substituted C _1-3 archeterocyclyl, or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, and nitrogen. , Oxygen, and sulfur to form a optionally substituted five- or six-membered ring containing one or two heteroatoms optionally selected.

In a particular embodiment of formula (I), if Z ² is CR ³ , R ³ is H, and R ⁴ is halogen (eg, chloro), then Z ¹ is -OR ⁷ , -N. (R ⁷ ) R ¹⁰ , -SR ⁷ , or -C (R ⁷ ) (R ¹⁰ ) R ¹¹ , where R ⁷ is optionally substituted C _1-3 arccycloalkyl, or One of C _1-3 archeterocyclyls optionally substituted, or R ⁷ and R ⁸ bonded together with the atom to which each is bonded, selected from nitrogen, oxygen, and sulfur. Alternatively, it forms a optionally substituted 5- or 6-membered ring containing two heteroatoms.

で表される基を形成する場合、Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでない。 In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Equation (IIa):

When forming a group represented by, R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl. , 2-Hydroxyethyl, 2-oxo-propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not a substituted alkyl, an unsubstituted alkyl, or an unsubstituted C ₂ arc heteroaryl.

In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Therefore, when forming a group represented by the formula (IIa), R ⁷ is not an alkyl or unsubstituted C ₂ arc heteroaryl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not a substituted alkyl, an unsubstituted alkyl, or an unsubstituted C ₂ archeterocyclyl.

In another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not an alkyl or a C ₂ arc heterocyclyl.

In yet another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are. When bonded to form a group represented by formula (IIa), R ⁷ and R ⁸ are bonded together with the atom to which they are bonded and selected from nitrogen, oxygen, and sulfur1 It forms a five- or six-membered ring that is optionally substituted and optionally contains one or two heteroatoms.

In yet another embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ² is CR ³ , and R ³ and R ⁴ are combined to form formula (IIa). When forming the represented group, Z is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

In certain embodiments of formula (I), each R ⁵ and R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. When forming the group represented by (IIa), R ⁷ is not methyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIa), R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1). -Il) ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl- Not isooxazole-3-yl-methyl, 4-methyl-imidazole-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by formula (IIa), R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheteroaryl, or a substituted alkheteroaryl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIa), R ⁷ is not an unsubstituted alkyl, a substituted alkyl, an unsubstituted alkheterocyclyl, or a substituted alkheterocyclyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −. If Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁹ is ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobuta. Not dienylaminocarbonyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −. If Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIa), then R ⁹ is H or -C (O) -N (H). )-(Linear C _1-3 alkyl).

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is halo, Z ² is CR ³ , and R ³ and R ⁴ are combined to represent a group of formula (IIa). If Z is -OR ⁷ and R ⁷ is not methyl or 2-chloroethyl, R ⁹ is H or -C (O) -N (H)-(linear C _1-3). Alkyl).

In certain embodiments of formula (I), R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. When forming a group represented by the formula (IIa), R ⁷ is not methyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIa), R ⁷ is not methyl.

で表される基を形成する場合、Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IIb) or (IIc)

When forming a group represented by, R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIb) or (IIc), R ⁷ and R ⁸ are bonded together with the atom to which each is bonded and selected from nitrogen, oxygen, and sulfur1 It forms a five- or six-membered ring that is optionally substituted and optionally contains one or two heteroatoms.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ² is CR ³ , and R ³ and R ⁴ are combined to form formula (IIb) or (IIc). When forming the represented group, Z ¹ is −OR ⁷ and R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −.

で表される基を形成する場合、Ｒ⁶がブロモでない。 In certain embodiments of formula (I), R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Equation (IIIa)

When forming a group represented by, R ⁶ is not bromo.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIIa), R ⁷ is not isopropyl, 3,3,3-trifluoropropyl, or 2- (N, N-dimethylamino) ethyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IIIa), R ⁸ is not H.

In certain embodiments of formula (I), where Z ² is CR ³ and R ³ and R ⁴ combine to form a group represented by formula (IIIa), then R ⁵ and R ⁶ respectively. Chloro, and R ⁷ is methyl, and R ⁸ is H, or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, choosing from nitrogen, oxygen, and sulfur. It forms a optionally substituted five- or six-membered ring that optionally contains one or two heteroatoms.

で表される基を形成する場合、Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでない。 In another embodiment of formula (I), R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, equation (IIIb):

When forming a group represented by, neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IIIb), each R ¹ and R ² is H.

で表される基を形成する場合、Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVa):

When forming the group represented by, R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidine-4-yl, 2- (1-). Not methyl-pyrrolidin-2-yl) ethyl or 3- (N, N-diethylamino) propyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVa), R ⁷ is not a substituted alkyl, heterocyclyl, alkheterocyclyl, or alkaline.

で表される基を形成する場合、Ｒ⁷が、２−メトキシエチルまたはベンジルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVb):

When forming a group represented by, R ⁷ is not 2-methoxyethyl or benzyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVb), R ⁷ is not a substituted alkyl or alkaline.

で表される基を形成する場合、Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVc):

When forming a group represented by, R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVc), R ⁷ is not a substituted alkyl.

で表される基を形成する場合、Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでない。 In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. Equation (IVd):

When forming a group represented by, R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl.

In a particular embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVd), R ⁷ is not a substituted alkyl or alkheterocyclyl.

で表される基を形成する場合、Ｒ⁷がベンジルでない。 In certain embodiments of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined to form the formula. (IVe) or (IVf):

When forming a group represented by, R ⁷ is not benzyl.

In another embodiment of formula (I), each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are combined. When forming a group represented by the formula (IVe) or (IVf), R ⁷ is not alkaline.

で表される基を形成する場合、Ｒ⁷がメチルでない。 In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, the formula (IVg), (IVh), (IVi), (IVj), or (IVk):

When forming a group represented by, R ⁷ is not methyl.

In a particular embodiment of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. Then, when forming a group represented by the formula (IVg), (IVh), (IVi), (IVj), or (IVk), R ⁷ is not alkyl.

In certain embodiments of formula (I), R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , Z ² is CR ³ , and R ³ and R ⁴ are bound. When forming a group represented by the formula (IVg), (IVh), (IVi), (IVj), or (IVk), R ⁷ and R ⁸ are combined with the atom to which each is bonded. They combine to form an optionally substituted five- or six-membered ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In a particular embodiment of formula (I), if R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ , and Z ² is CR ³ , then R ³ and R ⁴ are. , (IVg), (IVh), (IVi), (IVj), or (IVk) do not bind to form a group.

In a particular embodiment of formula (I), if R ⁶ is methyl, then each R ¹ and R ² is H.

In a particular embodiment of formula (I), if R ³ is H and each R ⁵ and R ⁶ is chloro, then R ⁷ is not methyl.

を有するか、またはその薬学的に許容できる塩である）。 In a particular embodiment of formula (I), R ^m is H (eg, a compound of formula (I) has the following structure:

Or is a pharmaceutically acceptable salt thereof).

In certain embodiments of formula (I), in certain embodiments of the methods of the invention, substituents are defined as described herein. In certain embodiments of the method of the invention, the method comprises administering to a mammal an effective amount of a compound of formula (I). In certain embodiments of the method of the invention, the method comprises administering to a mammal an effective amount of a compound of formula (Ib). In another embodiment, the method comprises administering to the mammal an effective amount of the compound of formula (Va). In certain embodiments, the method comprises administering to the mammal an effective amount of a compound of formula (Vb). In certain embodiments, the compound is one of Table 2 (eg, Compounds 2, 5-16, 18-27, 29, 33-36, 40-48, and 58-77, or pharmaceutically thereof. Can be selected from acceptable salts). In a further embodiment, the method comprises administering to the mammal an effective amount of Compound 38 or 39 or a pharmaceutically acceptable salt thereof.

In certain embodiments of the methods of the invention, the method comprises administering to a mammal a compound of formula (I) (eg, formula (Ia), (Ib), (Va), or (Vb)). Includes the step of treating mammals with neurodegenerative diseases.

In certain embodiments, the disease is a neurodegenerative disease (eg, tauopathy). Neurodegenerative diseases can be Alzheimer's disease, Huntington's disease, progressive supraclavicular paralysis, Parkinsonism, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia. Preferably, the neurodegenerative disease is Alzheimer's disease. In other embodiments, the disease is a proliferative disorder (eg, cancer, eg, acute myelogenous leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cells). Lung cancer, kidney cancer, small cell lung cancer, acute chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, recurrent multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, Small bowel cancer, or solid tumor).

In certain embodiments, the disease is an inflammatory or autoimmune disease (eg, rheumatoid arthritis, systemic lupus erythematosus, or asthma). In certain embodiments, the disease is a cardiovascular disease (eg, atherosclerosis or cardiomyopathy). In other embodiments, the disease is an allergy.

In yet another embodiment, the invention is an infectious disease of a mammal by administering to the mammal an effective amount of a compound of the invention (eg, a compound of the embodiment described above, or a pharmaceutically acceptable salt thereof). It features a method of treating.

In certain embodiments, the infection is a viral infection. In certain embodiments, the viral infection is a Herpesviridae virus (eg, simple herpesvirus type 1, simple herpesvirus type 2, herpes herpesvirus type 5, caposyloma-related herpesvirus, varicella virus. , Or Epstein-Barvirus), Polyomaviridae virus (eg, SV40), Poxviridae virus (eg, vaccinia virus), Leoviridae (eg, rotavirus) , Birnaviridae virus (eg, infectious Fabricius cyst virus), Picornaviridae virus (eg, poliovirus, rhinovirus, or coxsackie virus), Flaviviridae Virus (eg, hepatitis C virus or dengue virus), Arenaviridae virus (eg, lymphocytic choriomyelitis virus), Hepeviridae virus (eg, hepatitis E virus), Rabdo Viral family (Rhabdoviridae) virus (eg, bullous stomatitis virus), Paramixyviridae virus (eg, human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus), Bunyaviridae virus (eg, lacrossvirus), Orthomoxyviridae virus (eg, influenza A virus), Firoviridae virus (eg, Ebola virus) , Retroviridae (eg, HTLV1 or HIV1), or Hepadnaviridae (eg, hepatitis B virus).

In certain embodiments, the infectious disease is a fungal infection (eg, Candida albicans, Aspergillus fumigates, or Pneumocystis jiroveci).

In other embodiments, the infection is a bacterial infection (eg, acid-fast bacilli, anthrax, or bacterial pneumonia).

In an embodiment of any aspect of the method of the invention, the compound is orally, sublingually, orally, transdermally, intradermally, intramuscularly, parenterally, intravenously. It is administered intra-arterial, intracranial, subcutaneously, intraorbitally, intraventricularly, intrathecally, intraperitoneally, intranasally, by inhalation, and topically. Preferably, the compound is administered orally.

In certain embodiments of any aspect of the methods of the invention, the mammal is a human.

In a further aspect, the invention features a method of inhibiting Hsp90 by contacting cells with a compound of the invention, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method is performed in vitro. In other embodiments, the method is performed in vivo.

In another aspect, the invention
(I) With the pharmaceutical composition of the present invention;
(Ii) It features a kit containing instructions for use of the pharmaceutical composition of (i) for treating a disease of a mammal (eg, human) caused by the action of Hsp90.

In yet another aspect, the invention features compounds of the invention for use in treating diseases caused by the action of heat shock protein 90 (Hsp90). In certain embodiments of this aspect, the disease is any one of the diseases described in the aspects that characterize the methods of the invention. In a related aspect, the invention features compounds of the invention for use in treating infectious diseases. In a particular embodiment of this aspect, the infectious disease is any one of the infectious diseases described in the aspects that characterize the methods of the invention.

In yet another aspect, the invention features the use of compounds of the invention in the treatment of diseases caused by the action of heat shock protein 90 (Hsp90). In certain embodiments of this aspect, the disease can be any one of the diseases described in aspects that characterize the methods of the invention. In a related aspect, the invention features the use of the compounds of the invention in the treatment of infectious diseases. In a particular embodiment of this aspect, the infectious disease is any one of the infectious diseases described in the aspects that characterize the methods of the invention.

In a further aspect, the invention features the use of the compounds of the invention in the manufacture of agents for treating diseases caused by the action of heat shock protein 90 (Hsp90). In certain embodiments of this aspect, the disease can be any one of the diseases described in aspects that characterize the methods of the invention. In a related aspect, the invention is characterized by the use of the compounds of the invention in the manufacture of agents for treating infectious diseases. In a particular embodiment of this aspect, the infectious disease is any one of the infectious diseases described in the aspects that characterize the methods of the invention.

Definition Chemical Substituent The term "about" as used herein represents a value of ± 10% of the value stated.

The terms "acyl" or "alkanoyl" as used synonymously herein are attached to a parent molecular group via an alkyl group as defined herein or a carbonyl group as defined herein. Represents a hydrogen, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. An exemplary unsubstituted acyl group contains 2-7 carbons. Acyls can be unsubstituted or substituted, as defined for alkyl.

The term "alkali" as defined herein refers to a chemical substituent of the formula- (alkylene)-(aryl), where each group is as defined herein and is each. It can be substituted or unsubstituted according to each definition.

The term "alkheterocyclyl" as defined herein refers to a chemical substituent of the formula- (alkylene)-(heterocyclyl), where each group is as defined herein and is each. It can be substituted or unsubstituted according to each definition.

As used herein, the term "alkoxy" refers to a chemical substituent of formula-OR, where R is a C _1-6 alkyl group unless otherwise specified (eg, R is). , C _1-3 alkyl). Alkoxy can be unsubstituted or (1) 1 to 6 carbon alkoxy; (2) hydroxyl; (3) amino; (4) 1 to 6 carbon alkylamino; (5) dialkylamino. (Here, each of the alkyl groups is independently 1 to 6 carbons); (6) 3 to 8 carbon cycloalkyl; (7) oxo; (8) hal; (9). Alkoxysulfonyl with 1 to 6 carbon atoms; (10) Thioalkoxy with 1 to 6 carbon atoms; (11) aryl; (12) -CO ₂ ^RA (where ^RA is (a) hydrogen , (B) Alkoxy, (c) Cycloalkyl, (d) Alkoxyalkyl, and (e) Alkoxyl, where the alkylene group has 1 to 6 carbon atoms); or (13) -C (O) NR B R C ( where each of R ^B and R ^C are independently, (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alk One, two, or independently selected from the group consisting of cycloalkyl, and (e) alkaline, where the alkylene group has 1 to 6 carbon atoms). It may be substituted with three substituents; however, one or less substituents (2)-(5) may be bonded to a single carbon atom of the alkyl group, and substituents (2)-(2)-. None of (5) may be bonded to the carbon bonded to the oxygen atom of the alkoxy group. One or less oxo substituents may be attached to a single carbon of the alkoxy group, or two or less oxo substituents may be found in any of the alkoxy groups defined herein. Good.

The term "alkoxyalkyl" as used herein refers to an alkyl group substituted with an alkoxy group. An exemplary unsubstituted alkoxyalkyl group contains 2-9 carbons. In certain embodiments, the alkyl and the alkoxy can be further substituted with one, two, three, four, or five substituents as defined herein for each group, respectively.

The term "alkyl" as used herein refers to both linear and branched-chain saturated groups of 1 to 6 carbons (eg, 1 to 3 carbons) unless otherwise specified. including. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, and unless otherwise specified, (1) 1 to 6 carbon alkoxy; (2) hydroxyl; (3) amino; (4) 1 to Alkylamino of 6 carbons; (5) Dialkylamino (where each of the alkyl groups is 1 to 6 carbons independently); (6) Cycloalkyl of 3 to 8 carbons; (7) Oxo; (8) hal; (9) Alkylsulfonyl with 1 to 6 carbon atoms; (10) Thioalkoxy with 1 to 6 carbon atoms; (11) Aryl; (12) -CO ₂ R ^A (where ^RA is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkcycloalkyl, and (e) alkalil, where the alkylene group has from 1 to 6 carbon atoms); (13) -C (O ) NR B R C ( where each of R ^B and R ^C are independently, (a) hydrogen, (b) alkyl is selected from the group consisting of (c) cycloalkyl, (d) alkcycloalkyl, and (e) alkaryl, where the alkylene group has 1 to 6 carbon atoms, or R ^B and, R ^C are bonded, C _{2 to 9} heterocyclyl the formed); one selected and (14) independently from the group consisting of cyano, two, three, or two or more carbon alkyl In the case of a group, it may be optionally substituted with four substituents; however, one or less substituents (2)-(5) may be attached to a single carbon atom of the alkyl group. One or less oxo substituents may be attached to a single carbon of the alkyl group, or two or less oxo substituents may be found in any of the alkyl groups defined herein. Good.

As used herein, the term "alkylene" and the prefix "alk-" are saturated derived from linear or branched saturated hydrocarbons by the removal of two hydrogen atoms. It represents a divalent C _{1 to 10} hydrocarbon group and is exemplified by methylene, ethylene, propylene, isopropylene and the like. The term "C _{x to y} alkylene" and the prefix "C _xy alk -" represents an alkylene group having x to y carbons. Illustrative values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, or 10. is there. In certain embodiments, the alkylene can be further substituted with one, two, three, or four substituents as defined herein for the alkyl group.

As used herein, the term "alkylsulfonyl" refers to an alkyl group attached to a parent molecular group via a -S (O) ₂ -group. An exemplary unsubstituted alkylsulfonyl group has 1 to 6 carbons. In certain embodiments, the alkyl group can be further substituted with one, two, three, or four substituents as defined herein.

The term "amino" as used herein refers to a chemical substituent of formula-NH ₂ . The amino group may be mono-substituted with, for example, an alkyl, alkanoyl, aryl, allylloyl, cycloalkyl, heterocyclyl, or alkheterocyclyl group (eg, an "alkylamino" having the formula -NH- (optionally substituted). C _1-6 alkyl), eg-NH- (unsubstituted C _1-6 alkyl)), or, eg, disubstituted with alkyl, alkanoyl, aryl, aryloyl, cycloalkyl, heterocyclyl, or alkheterocyclyl groups. Good (eg, the formula -NR'R "(where R'and R" are each independently and optionally substituted C _1-6 alkyl), eg-NR'R ". (Here, each of _{R'and R'is} independently unsubstituted C _1-6 alkyl) "dialkylamino"). The C _1-6 alkyl group optionally substituted can be a C _1-6 haloalkyl, for example C _1-6 fluoroalkyl.

As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. Each of the alkyl and amino groups can be independently substituted or unsubstituted as defined herein for each respective group.

The term "aryl" as used herein is a monocyclic, bicyclic, or polycyclic carbon ring having 3 to 12 carbons and having one or two aromatic rings. Represents a system. Non-limiting examples of aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. Aryl groups are (1) 1 to 6 carbon alkyl; (2) 1 to 6 carbon alkoxy; (3) hydroxyl; (4) amino; (5) 1 to 6 carbon alkyl amino. (6) Dialkylamino (where each of the alkyl groups is independently 1 to 6 carbons); (7) 3 to 8 carbons of cycloalkyl; (8) oxo; (9) ) Hal; (10) Alkylsulfonyl with 1 to 6 carbon atoms; (11) Thioalkoxy with 1 to 6 carbon atoms; (12) Aryl; (13) Alkyl (where the alkylene group is 1 ~ 6 carbon atoms); (14) -CO ₂ ^RA (where ^RA is (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkalil, and (e) is selected from the group consisting of hydrogen, where the alkylene group has 1-6 carbon atoms); and (15) -C (O) NR B R C ( where, R ^B and each R ^C is independently selected from (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, the group consisting of (d) alkaryl, and (e) hydrogen, where the alkylene The group can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of (having 1 to 6 carbon atoms).

As used herein, the term "allyloyl" refers to an aryl group attached to a parent molecular group via an alkyl group.

As used herein, the term "carbonyl" refers to a C (O) group, which can also be expressed as C = O, and is derived from a combination of a tetravalent carbon atom and an oxo substituent.

The term "cyano" as used herein refers to a -CN group.

As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with cyano. An exemplary unsubstituted cyanoalkyl group contains 2-9 carbons. In certain embodiments, the alkyl group may be further substituted with one, two, three, four, or five substituents as defined herein for each group.

As used herein, the term "cycloalkyl" represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of 3 to 8 carbons, unless otherwise specified, cyclopropyl, cyclobutyl. , Cyclopentyl, Cyclohexyl, Cycloheptyl, Bicyclo [2.2.1. ] Illustrated by Heptil and the like. Cycloalkyl groups include, for example, (1) 1 to 6 carbon alkyl; (2) 1 to 6 carbon alkoxy; (3) hydroxyl; (4) amino; (5) 1 to 6 carbon. Alkylamino; (6) Dialkylamino (where each of the alkyl groups is independently 1 to 6 carbons); (7) Cycloalkyl of 3 to 8 carbons; (8) Oxo (9) Halo; (10) Alkylsulfonyl with 1 to 6 carbon atoms; (11) Thioalkoxy with 1 to 6 carbon atoms; (12) Aryl; (13) Alkyl (where alkylene group) Is 1 to 6 carbon atoms); (14) -CO ₂ ^RA (where ^RA is (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) is selected from alkaryl, and (e) the group consisting of hydrogen, where the alkylene group has 1-6 carbon atoms); or (15) -C (O) NR B R C ( where, Each of R ^B and ^RC is independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaline, and (e) hydrogen. in the alkylene group has from 1 to 6 carbon atoms, or by bonding R ^B and R ^C, one independently selected from the group consisting of forming a C _{2 to 9} heterocyclyl), It can be optionally substituted with 2, 3, or 4 substituents.

As used herein, the term "five-membered ring" refers to a saturated or unsaturated aromatic or non-aromatic group having five atoms in a cyclic configuration, where, unless otherwise specified, 4 One atom is carbon and the remaining atoms are selected from the group consisting of carbon, nitrogen, sulfur, and oxygen. The five-membered ring can be fused to another cyclic group selected from heterocyclyl, heteroaryl, cycloalkyl, and aryl. The five-membered ring is unsubstituted or, for example, (1) 1 to 6 carbon alkoxy; (2) hydroxyl; (3) amino; (4) 1 to 6 carbon alkylamino; ( 5) Dialkylamino (where each of the alkyl groups is independently 1 to 6 carbons); (6) 3 to 8 carbons of cycloalkyl; (7) oxo; (8) 1 ~ 6 carbon atom alkylsulfonyl; (9) 1-6 carbon atom thioalkoxy; (10) aryl; (11) alkaline (where the alkylene group is 1-6 carbon atoms There are; (12) optionally substituted alkyls of 1 to 6 carbons (eg, unsubstituted alkyls, alkoxyalkyls, hydroxyalkyls, haloalkyls, or cyanoalkyls); (13) -CO ₂ ^RA (13) -CO ₂ ^RA ( Here, ^RA is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkylcycloalkyl, (d) alkalil, and (e) hydrogen, where the alkylene group is: having from 1 to 6 carbon atoms); (14) -C (O ) NR B R C ( where each of R ^B and R ^C are independently, (a) is optionally substituted Alkyl (eg, unsubstituted alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, or cyanoalkyl), (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaline, (e) heterocyclyl, (f) alkheterocyclyl , (g) alkoxy, and (h) is selected from the group consisting of hydrogen, where the alkylene group has from 1 to 6 carbon atoms, or by bonding R ^B and R ^C, _{C. 2 to 9} heterocyclyls are formed); and (15) can be substituted with one, two, three, or four substituents independently selected from the group consisting of cyano.

The term "fluoroalkyl" as used herein refers to an alkyl group as defined herein, wherein one or more hydrogen radicals (eg, one) attached to the alkyl group. 2, 3, 4, or 5 or more hydrogen radicals) are replaced with fluorine radicals. In certain embodiments, the fluoroalkyl group can be perfluoroalkyl. The prefix "fluoro" indicates that the corresponding group is substituted with one or more (eg, one, two, three, four, or five or more) fluorine radicals.

The term "haloalkyl" as used herein refers to an alkyl group as defined herein, substituted with a halogen group (ie, F, Cl, Br, or I). C _1-6 haloalkyls can be substituted with 4 or 5 halogens in the case of one, two, three, or two or more carbon alkyl groups. The haloalkyl group comprises a perfluoroalkyl. In certain embodiments, the haloalkyl is a fluoroalkyl. In certain embodiments, the C _1-6 haloalkyl groups can be further substituted with one, two, three, or four substituents described herein for the alkyl group.

The terms "halogen," "hal," or "halo," used synonymously herein, are fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I). Represents a group selected from. The prefix "halo" indicates that the relevant group is replaced with a halogen group (ie, F, Cl, Br, or I).

As used herein, the term "heterocyclyl" is one, two, three, or four independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified. Represents a 5-membered, 6-membered or 7-membered ring containing a heteroatom. The 5-membered ring has 0 to 2 double bonds, and the 6 and 7 membered rings have 0 to 3 double bonds. The term "heterocyclyl" also refers to a crosslinked polycyclic structure in which one or more carbons and / or heteroatoms crosslink two non-adjacent members of a monocyclic ring, eg, a heterocyclic compound having a quinuclidinyl group. .. The term "heterocyclyl" refers to any of the above heterocycles being one, two, or three carbocycles, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another single. It also includes bicyclic, tricyclic, and tetracyclic groups fused to cyclic heterocycles, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples of condensed heterocyclyls include tropane and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclyls include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolydinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolinyl. Thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indrill, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, frill, thienyl, thiazolidinyl, isothiazolyl, isoindazolyl, triazolyl, tetrazolyl, oxadiazolyl Examples thereof include thiadiazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindrill, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclyl groups are (1) 1 to 6 carbon alkyl; (2) 1 to 6 carbon alkoxy; (3) hydroxyl; (4) amino; (5) 1 to 6 carbon alkyl amino. (6) Dialkylamino (where each of the alkyl groups is independently 1 to 6 carbons); (7) 3 to 8 carbons of cycloalkyl; (8) oxo; (9) ) hal; (10) alkylsulfonyl having 1 to 6 carbon atoms; (11) thioalkoxy of one to six carbon atoms; (12) aryl; (13) alkaryl, (14) -CO ₂ R ^a (Here, ^RA is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaline, and (e) hydrogen, where the alkylene group is has from 1 to 6 carbon atoms); or (15) -C (O) NR B R C ( where each of R ^B and R ^C are independently, (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, is selected from the group consisting of (d) alkaryl, and (e) hydrogen, where the alkylene group has 1 to 6 carbon atoms, or R ^B and, ^RC binds to form C _2-9 heterocyclyls) and is optionally substituted with one, two, three, four, or five substituents selected independently. obtain.

As used herein, the term "heteroaryl" refers to a subset of heterocyclyls defined herein that are aromatics: they are monocyclic or polycyclic ring systems. It contains 4n + 2 π electrons. In certain embodiments, heteroaryls are, for example, (1) alkyls of 1 to 6 carbons; (2) alkoxys of 1 to 6 carbons; (3) hydroxyls; (4) aminos; (5) 1 to 1 6-carbon alkylamino; (6) dialkylamino (where each of the alkyl groups is 1 to 6 carbons independently); (7) 3-8 carbon cycloalkyl; (8) Oxo; (9) hal; (10) Alkylsulfonyl with 1 to 6 carbon atoms; (11) Thioalkoxy with 1 to 6 carbon atoms; (12) Aryl; (13) Alkyl; 14) -CO ₂ ^RA (where ^RA is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkalil, and (e) hydrogen. wherein the alkylene group has 1-6 carbon atoms); or (15) -C (O) NR ^B R ^C (where each of R ^B and R ^C are independently ( Selected from the group consisting of a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkalil, and (e) hydrogen, where the alkylene group contains 1 to 6 carbon atoms. It is substituted with one, two, three, or four substituents independently selected from the group consisting of).

The term "hydroxy" as used herein refers to a -OH group.

The term "hydroxyalkyl" as used herein refers to an alkyl group as defined herein, substituted with one or two hydroxy groups, provided that no more than one hydroxy group is present. , May be bonded to a single carbon atom of the alkyl group, exemplified by hydroxymethyl, dihydroxypropyl and the like.

As used herein, the term "N-protected amino" refers to an amino group as defined herein to which an N-protecting group is attached, as defined herein.

As used herein, the term "N-protecting group" refers to a group intended to protect an amino group from unwanted reactions during the synthetic procedure. N- protecting groups which are commonly used, Greene, incorporated herein by reference, Protective Groups in Organic Synthesis, 3 rd Edition (John Wiley & Sons, New York, 1999) which is incorporated herein by reference. N-protecting groups include acyl, aroyl, or carbamil groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o. -Nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliary groups such as protected or unprotected D, L or D, L-amino acids, such as alanine. , Leucine, phenylalanine, etc .; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, etc .; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl. , 2-Nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2 -Nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyl Oxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro Arylalkyl groups such as phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl such as benzyl, triphenylmethyl, benzyloxymethyl and silyl groups such as trimethylsilyl And so on. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

As used herein, the term "six-membered ring" refers to a saturated or unsaturated aromatic or non-aromatic group having six atoms in a cyclic configuration, where 5 unless otherwise specified. One atom is carbon and the remaining atoms are selected from the group consisting of carbon, nitrogen, sulfur, and oxygen. The six-membered ring can be fused to another cyclic group selected from heterocyclyl, heteroaryl, cycloalkyl, and aryl. The six-membered ring is unsubstituted or, for example, (1) alkyl of 1 to 6 carbons; (2) alkoxy of 1 to 6 carbons; (3) hydroxyl; (4) amino; (5) amino. ) 1 to 6 carbons of alkylamino; (6) dialkylamino (where each of the alkyl groups is independently 1 to 6 carbons); (7) of 6 to 8 carbons Cycloalkyl; (8) oxo; (9) alkylsulfonyl with 1 to 6 carbon atoms; (10) thioalkoxy with 1 to 6 carbon atoms; (11) aryl; (12) alkaline (here, The alkylene group is 1 to 6 carbon atoms); (13) -CO ₂ ^RA (where ^RA is (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (where ^RA is). d) alkaryl, and (e) is selected from the group consisting of hydrogen, where the alkylene group has 1 to 6 carbon atoms); (14) -C (O ) NR B R C ( where , R ^B and ^RC , respectively, are independently selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaline, and (e) hydrogen. here, the alkylene group has from 1 to 6 carbon atoms, or by bonding R ^B and R ^C, to form a C _{2 to 9} heterocyclyl); and (15) independently from the group consisting of cyano Can be substituted with one, two, three, or four substituents selected.

As used herein, the term "thioalkoxy" refers to a chemical substituent of formula-SR, where R is an alkyl group. In certain embodiments, the alkyl group may be further substituted with one, two, three, or four substituents described herein for the alkyl group.

The term "thiol" as used herein refers to a chemical substituent of formula-SH.

例えば、「Ｒ³およびＲ⁴が結合して、−Ｎ（Ｒ⁹）−ＣＨ＝ＣＨ−を形成する」という記述は、−Ｎ（Ｒ⁹）−ＣＨ＝ＣＨ−の窒素原子が、Ｃ⁵炭素またはＣ⁶炭素のいずれかに近接し得ることを示す。「−Ｎ（Ｒ⁹）−ＣＨ＝ＣＨ−の窒素原子が、Ｃ⁵に近接している」と組み合わせた「Ｒ³およびＲ⁴が結合して、−Ｎ（Ｒ⁹）−ＣＨ＝ＣＨ−を形成する」という記述は、以下の化合物を示す。

When referring to numbered positions within the compounds of the invention, the following numbering system is used:

For example, in the description that "R ³ and R ⁴ combine to form -N (R ⁹ ) -CH = CH-", the nitrogen atom of -N (R ⁹ ) -CH = CH- is C ⁵ Indicates that it can be close to either carbon or C ⁶ carbon. Combined with "the nitrogen atom of -N (R ⁹ ) -CH = CH- is close to C ⁵ ", "R ³ and R ⁴ are combined and -N (R ⁹ ) -CH = CH- The statement "forms" refers to the following compounds:

The asymmetric center or chiral center can be present in any of the compounds of the invention. The present invention envisions various stereoisomers and mixtures thereof. The individual stereoisomers of the compounds of the invention are synthetically derived from commercially available starting materials containing asymmetric or chiral centers, or by the preparation of a mixture of enantiomeric compounds followed by degradation well known to those skilled in the art. Prepared. These decomposition methods are: (1) Separation and assistance of diastereomers obtained by binding, recrystallization or chromatography of a racemic mixture of enantiomers to a chiral auxiliary represented by (+/-). Illustrated by liberation of optically pure products from groups or by direct separation of (2) a mixture of optical enantiomers on a chiral chromatography column or by a chiral HPLC method. The method of chiral separation has already been described (GB Cox (ed.) In Preparative Enantioselective Chromatography, 2005, Blackwell Publishing). Alternatively, the chiral compound can be prepared by asymmetric synthesis, which is advantageous for the preparation of superimposing one enantiomer on top of another. Alternatively, a chiral pool synthesis (starting from an enantiomerically pure component) in which the chiral group or chiral center is retained in the intermediate or final product can be used. The enantiomers are represented herein by the reference numerals "R" or "S", depending on the configuration of the substituents around the chiral atom. Alternatively, the enantiomer is represented as (+) or (−), depending on whether the solution of the enantiomer rotates clockwise or counterclockwise in the plane of polarization.

Also, geometric isomers may be present in the compounds of the present invention. The present invention envisions various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds, such isomers being referred to as Z or E configurations, where The term "Z" represents a substituent on the same side of a carbon-carbon double bond, and the term "E" represents a substituent on the opposite side of a carbon-carbon double bond. It is also recognized that in the case of a structure in which multiple tautomers are possible, the description of one tautomer corresponds to both explanations, unless otherwise specified.

Each position in the compounds of the invention may contain elements with natural isotopic abundance. Alternatively, one or more positions in the compounds of the invention may contain abundant elements in natural or synthetic isotopes. For example, one or more positions of the compounds of the invention, including hydrogen, can be, for example, deuterium or tritium rich. In certain embodiments, one or more positions of the compounds of the invention containing carbon can be, for example, rich in ¹⁴ C or ¹³ C. In other embodiments, the position of one or more of the compounds of the invention, including nitrogen, can be, for example, rich in ¹⁵ N. In certain embodiments, the position of one or more of the compounds of the invention, including oxygen, can be, for example, rich in ¹⁸ O, ¹⁷ O, or ¹⁵ O. In certain embodiments, one or more positions of the compounds of the invention containing fluorine, for example, ¹⁸ F it may be abundant. In other embodiments, one or more positions of the compounds of the invention, including carbon, can be abundant, for example, ³² S, ³³ S, ³⁴ S, ³⁵ S, or ³⁶ S. In yet other embodiments, one or more positions of the compounds of the invention, including chlorine, can be, for example, rich in ³⁵ Cl, ³⁶ Cl, or ³⁷ Cl.

Some abbreviations used herein:
BINAP-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl;
t-Bu-tert-butyl or 1,1-dimethylethyl;
cat-catecholate;
dppb-bis (diphenylphosphino) butane;
dppf-bis (diphenylphosphino) ferrocene;
Et-Ethyl;
Me-methyl;
OAc-acetate;
OMs-mesylate or methanesulfonate;
ONf-nonafrate or nonafluoro-n-butyl sulfonate;
OTf-triflate or trifluoromethanesulfonate;
pin-pinacolat;
i-Pr-isopropyl or 1-methylethyl; and n-Pr-n-propyl;
SIMes-1,3-bis (2,4,6-trimethylphenyl) imidazoline-2-iriden;
SIPr-1,3,-bis (2,6-diisopropylphenyl) imidazolin-2-iriden; and THF-tetrahydrofuran.

Other term The term "about" is used herein to mean a value of ± 10% of the stated value.

The terms "effective amount" or "effective amount for" or "therapeutically effective amount" refer to a decrease in Hsp90 activity (eg, Hsp90) upon administration of a composition containing a desired result, eg, a compound of the invention. Inhibition of), increased expression of Hsp70, decreased aggregation of Aβ peptide (eg, inhibition of aggregation of Aβ peptide), increased degradation of Aβ peptide, and decreased phosphorylation of tau protein, and / or subject nerves. It means the amount of a compound of the invention sufficient to produce one or more of the relief or amelioration of symptoms of degenerative diseases (eg, Alzheimer's disease). The increase and decrease associated with administration of an effective amount of the compound are, where applicable, to the level or condition of the subject not receiving the compound of the invention, or to the subject prior to administration of the compound of the invention. is there.

As used herein, the term "element" refers to a substance consisting of a single type of atom, i.e., each nucleus of each atom of a single element contains the same number of protons.

As used herein, the term "neurodegeneration" refers to the progressive loss of neuronal structure or function, including neuronal death. The term "neurodegenerative disease" refers to a disease in which neurodegeneration is, at least in part, a cause, symptom, or phenotype.

As used interchangeably herein, the terms "patient" and "subject" refer to any animal (eg, a mammal, eg, a human). Subjects treated according to the methods described herein are those diagnosed with neurodegenerative diseases, such as tauopathy (eg, Alzheimer's disease), or proliferative disorders with such conditions, or such. Can be a subject at risk of developing various conditions. Diagnosis can be made by any method or technique known in the art. Those skilled in the art will test that subjects treated according to the present invention are undergoing standard testing or compared to levels in one or more risk factors, eg, samples derived from healthy subjects. Understand that increased levels of tau protein or increased levels of phosphorylated tau protein in body-derived samples (eg, cerebrospinal fluid) can be recognized as high-risk subjects without testing. Will do.

The term "pharmaceutical composition" as used herein is formulated with a pharmaceutically acceptable excipient and is part of a treatment program for the treatment of mammalian diseases of government regulators. Represents a composition containing a compound described herein, manufactured or sold with approval. The pharmaceutical composition is, for example, for oral administration in unit dosage form (eg, tablets, capsules, caplets, gel caps, or syrups); for topical administration (eg, as creams, gels, lotions, or ointments); intravenously. It can be formulated for administration (eg, as a sterile solution without microencapsulation and in a lotion suitable for intravenous use); or in any other formulation described herein.

The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used interchangeably herein are used herein to have properties that are non-toxic and non-inflammatory in patients. Refers to any component other than the listed compounds (eg, a vehicle capable of suspending and dissolving the active compound). Excipients include, for example: anti-caking agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), skin softeners, emulsifiers, fillers (diluents). Agents), coatings or coatings, flavors, fragrances, lubricants (fluidity improvers), lubricants, preservatives, printing inks, excipients, suspending agents or dispersants, sweeteners, or hydrated water. May include. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinylpyrrolidone, citric acid, crospovidone, cysteine. , Ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, magnesium stearate, martitol, mannitol, methionine, methyl cellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, alpha starch, propylparaben, palmitin Retinyl acid, cellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, And xylitol.

As used herein, the term "pharmaceutically acceptable prodrug" is, within reasonable medical judgment, commensurate with a reasonable risk / benefit ratio and valid for its intended use. Represents a prodrug of a compound of the invention suitable for use in contact with human and animal tissues with excessive toxicity, irritation, allergic reactions and the like.

The term "pharmaceutically acceptable salt" as used herein is, within reasonable medical judgment, commensurate with a reasonable risk / benefit ratio, excessive toxicity, irritation, allergic reaction, etc. Represents a salt suitable for use in contact with human and animal tissues without. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al. , J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and CG Vermus), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separated by reacting the free base group with a suitable organic acid. Typical acid addition salts include acetate, adipate, alginate, ascorbate, asparagate, benzenesulfonate, benzoate, bicarbonate, borate, butyrate, and cerebral acid salt. , Camper sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptone, hexane Acids, hydrobromates, hydrochlorides, hydrogen iodide, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonic acids Salt, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropi Onate, phosphate, picphosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Can be mentioned. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and, but not limited to, ammonium, tetramethylammonium, tetraethylammonium. , Methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

As used herein, the term "pharmaceutically acceptable solvate" means a compound described herein in which molecules of a suitable solvent are incorporated into a crystal lattice. Suitable solvents are physiologically acceptable at the doses administered. For example, the solvate can be prepared by crystallization, recrystallization, or precipitation from a solution containing an organic solvent, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (eg, monohydrate, dihydrate, and trihydrate), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), N, N'-dimethyl. Formamide (DMF), N, N'-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2- ( 1H) -pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate and the like. When water is the solvent, the molecule is called a "hydrate".

As used synonymously herein, the abbreviation "PSA" and the term "polar surface area" of a molecule are defined as the sum of the surface areas across all polar atoms. The unit of PSA is Å ² (square angstrom).

The term "preventing" as used herein refers to prophylactic treatment, i.e., a treatment that prevents one or more symptoms or conditions of a disease, disease, or condition described herein. .. Prophylactic treatment, including administration of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be acute, short-term, or chronic. The dose administered can vary during the course of prophylactic treatment.

As used herein, the term "prodrug" refers to a compound that is rapidly converted in the body to the parent compound of the above formula, for example, by hydrolysis in the blood. The prodrugs of the compounds described herein can be conventional esters. Some common esters used as prodrugs are phenyl esters, aliphatic (C _1- C ₈ or C _8- C ₂₄ ) esters, cholesterol esters, acyloxymethyl esters, carbamate, and amino acid esters. .. For example, a compound containing an OH group can be acylated at this position in its prodrug form. A full description is given in Higuchi and Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. et al. Roche, ed. , Bioreversible Carriers in Drug Design, American Pharmacists Association and Pergamon Press, 1987, and Judkins et al. , Synthetic Communications 26 (23): 4351-4637, 1996, each of which is incorporated herein by reference. Preferably, the prodrugs of the compounds of the invention are brought into contact with human and animal tissues with reasonable risk / benefit ratios and with excessive toxicity, irritation, allergic reactions, etc. that are effective for their intended use. It is suitable for use.

The term "proliferative disease" as used herein refers to both cancerous and non-cancerous diseases. Proliferative disorders are characterized by the disorderly proliferation of certain types of cells (eg, astrocytes). Preferably, the tumor cells associated with a proliferative disease (eg, cancer) respond to inhibition of Hsp90 by apoptosis. Proliferative disorders treated according to the methods of the invention using the compounds of the invention include gliomas, meningiomas, pituitary adenomas, schwannomas (eg, schwannomas or fibromas). obtain. Proliferative disorders within the scope of the present invention include cancers such as acute myelogenous leukemia, gastrointestinal stromal tumor, gastric cancer, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, kidney cancer, small cell lung cancer, Can be acute chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, recurrent multiple myeloma, refractory multiple myeloma, myeloproliferative disorder, pancreatic cancer, small bowel cancer, or solid tumor .. Preferably, the proliferative disorders treated with the compounds of the invention according to the methods of the invention may include brain tumors (eg, malignant brain tumors). For example, a brain tumor that can be treated with a blood-brain barrier penetrant compound of the invention can be a glioma or meningioma, in particular a glioma (eg, glioblastoma), or a malignant form thereof. Cancers that can be treated according to the present invention can also be cancers that have metastasized to the brain (eg, lung cancer, breast cancer, melanoma, colon cancer, kidney cancer, and thyroid cancer).

As used herein and well understood in the art, "treatment" is a technique for obtaining beneficial or desired results, such as clinical results. Beneficial or desired outcomes, whether detectable or undetectable, alleviate or ameliorate one or more symptoms or conditions; reduce the degree of disease, disease, or condition; disease, Stabilized (ie, not exacerbated) condition of the disease or condition; prevention of metastasis of the disease, disease or condition; delay or slowing of progression of the disease, disease or condition; of the disease, disease or condition Improvement or alleviation; and can include remission (whether partial or complete remission). "Relieving" a disease, disease, or condition reduces and / or progresses the degree and / or unwanted clinical symptoms of the disease, disease, or condition compared to the degree or time course without treatment. Means that the time course of is slowed down or extended.

A 500 MHz ¹ H NMR spectrum of compound 20 in CDCl ₃ is shown. A 500 MHz ¹ H NMR spectrum of compound 34 in CDCl ₃ is shown. A 500 MHz ¹ H NMR spectrum of compound 36 in CDCl ₃ is shown. Five graphs showing IC ₅₀ data for compounds 20, 36, 37, and 39 and known Hsp90 inhibitors as measured using the fluorescence polarization assay described in Example 2 are shown. The graph which compares the relative bond / dissociation rate with respect to the concentration of compound 20 is shown. FIG. 6 is a photograph of a gel showing increased expression of Hsp70 at higher concentrations of compound 20 in a cell-based functional assay. Furthermore, FIG. 5B shows that the expression of Hsp90 remains unchanged with changes in the concentration of compound 20. FIG. 3 shows a histogram comparing cell viability% in cells contacted with viable cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor). FIG. 5 shows a graph comparing pTau231 levels in living cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor). FIG. 5 shows a graph comparing pTau396 levels in living cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor). The graph of the concentration of compound 20 in mouse plasma is shown. The data in this graph exclude the plasma concentration of compound 20 in animal IRN 12. The graph of the concentration of compound 20 in mouse plasma is shown. The data in this graph includes all mouse plasma data points. The graph of the concentration of compound 20 in a mouse brain tissue is shown. The data in this graph exclude the plasma concentration of compound 20 in animal IRN 12. The graph of the concentration of compound 20 in a mouse brain tissue is shown. The data in this graph includes all mouse brain tissue data points.

The present invention relates to novel aminopyrimidines and related compounds having Hsp90 inhibitory activity, pharmaceutical compositions containing them, and their medical uses (eg, proliferative disorders (eg, cancer) or neurodegenerative disorders (eg, eg). It is characterized by the treatment of tauopathy). In particular, the compounds of the present invention are capable of penetrating the blood-brain barrier. Thus, the medical uses of these compounds include diseases and conditions that affect the brain of mammals (eg, humans).

Compounds of the Invention An exemplary compound of the invention or a pharmaceutically acceptable salt thereof is shown in Table 2.

である。 Non-limiting examples of pharmaceutically acceptable salts of the compounds of the invention are:

Is.

Illustrative methods for synthesizing the compounds of the invention are described herein.

Methods for Preparing Compounds of the Invention For example, according to the reaction sequence shown in Scheme 1, the compounds of the present invention can be prepared by methods similar to those established in the art. The numbering system used in the general scheme does not necessarily correspond to those used herein or elsewhere in the claims.

As shown in Scheme 1, one method for reaching compound (C) of the present invention is a standard cross-coupling reaction (eg, Suzuki coupling, Hiyama coupling, still coupling, Negishi coupling, etc. The Tamao-Kumada coupling, or Murahashi coupling) is used, where the nucleating agent A and the electrophoretic agent B are metal salts such as palladium, copper, iron, or nickel salts (eg PdCl). ₂ , Pd (OAc) ₂ , CuBr, CuI, (CuOTf) ₂ -toluene complex, Fe (OTf) ₃ , FeCl ₃ , FeBr ₃ , NiCl ₂ , or NiBr ₂ ) are bound. Optionally, a ligand such as phosphine (eg PPh ₃ , P (2-frill) ₃ , P (t-Bu) ₃ , dppf, dppb, or BINAP), N-heterocyclic carbene (eg SIMes). Alternatively, SIPr), or di-pyridine (eg, 2,2'-bipyridyl or 1,10-phenanthroline) may be added to facilitate the reaction. Alternatively, an organometallic complex, such as Pd (PPh ₃ ) ₄ or (dppf) PdCl ₂ , can be used directly with or without additional ligands. Additives such as tetrabutylammonium fluoride, LiCl, KOAc, or AgOTf may be added to minimize dehalogenation or to promote the cross-coupling reaction. One of ordinary skill in the art will be able to determine a suitable solvent for the reaction by standard screening. Non-limiting examples of solvents used in the cross-coupling reaction are water, ethanol, acetone, tetrahydrofuran, toluene, 1,4-dioxane, and mixtures thereof. For non-limiting examples of conditions and catalysts that can be used to prepare compounds of the invention represented by formula C using cross-coupling chemistry, see Miyaura et al, incorporated herein by reference. .. , "Cross-Coupling Reactions: A Practical Guide" in Topics in Chemical Chemistry, Springer, 2002, and Nicolaou et al. , Angew. Chem. Int. Ed. , 44: 4442-4489, 2005. Alternatively, the compound of formula A may be an electrophile and has a leaving group X instead of M, while the compound of formula B may be a nucleophile and is a metal or metal instead of X. It has a semimetal group M.

The compounds of formula A can be subjected to any method known in the art, such as the subsequent addition of metal-halogen (eg, lithium-halogen) exchanges (boron-based, silicon-based, tin-based, zinc-based, or magnesium-based agents). With or without), preparation of Grignard reagents, Sandmeyer reaction, or cross-coupling with di-metalloid agents (eg, Miyaura boring reaction). Non-limiting examples of the preparation of A (Sandmeyer reaction and lithium halogen exchange to prepare E, and Miyaura boration reaction to prepare G) are shown in Scheme 2.

The compounds of formula B can be prepared according to any method known in the art, such as the Biginelli reaction followed by oxidation of the resulting 2-aminodihydropyrimidine derivative. Alternatively, the compound of formula B can be reached using the synthetic method overview in Scheme 3.

As shown in Scheme 3, the compound of formula H can be condensed with the compound of formula I to obtain the compound of formula J. The amino group of the 2-aminopyrimidine derivative J is then protected (P = divalent N-protecting group, two monovalent N-protecting groups, or one monovalent N-protecting group and one hydrogen. ), A compound of formula K can be obtained. The hydroxyl groups in the compounds of formula K are then subjected to, for example, dehydration-halogenation reagents (eg, POCl ₃ , PCl ₅ , SOCl ₂ , SO ₂ Cl ₂ , and according to any method known in the art. Their brominated or iodinated forms) can be used to convert to halogens in compounds of formula L. Alternatively, the hydroxyl group of the compound of formula K can be a reagent such as Tf ₂ O, PhNTf ₂ , PhNNf ₂ , or P (O) (OR) ₂ Cl, and optionally a base (eg Et ₃ N). , (IPr) ₂ NEt, or pyridine) and / or a catalyst (eg, 4-dimethylaminopyridine) can be used to convert to pseudohalogens in compounds of formula L. N- protecting group P is, methods known in the art (e.g., Greene, Protective Groups in Organic Synthesis , 3 rd Edition (John Wiley & Sons, New York, see 1999)) according to a cross cup shown in Scheme 1 It can be removed from compound L before or after the ring.

In the reactions described above, it may be necessary to protect reactive functional groups (eg, hydroxy, amino, thio, or carboxy groups) to avoid unwanted involvement in the reaction. The methods of incorporating such groups and the methods required to introduce and remove them are known to those of skill in the art (eg, Greene, supra). The deprotection step can be the final step in the synthesis such that removal of the protecting group results in the compound of formula (Ia) disclosed herein. The starting materials used in any of the above schemes are available for purchase or can be prepared using methods known to those of skill in the art, either by the methods described in the chemical literature or by conformance thereof. The order in which the steps are performed may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

Any compound of formula (I), (Ia), (Ib), (Va), or (Vb), or any of the intermediates described in the above schemes, is one known to those of skill in the art. Alternatively, it can be further derivatized using multiple standard synthetic methods. Such methods may include substitution, oxidation or reduction reactions. These methods also modify, introduce or remove the appropriate functional groups from compounds of formula (I), (Ia), (Ib), (Va), or (Vb), or any intermediate above. Can be used to obtain or denature the body. Specific substitution methods include alkylation, arylation, heteroaryllation, acylation, thioacylation, halide, sulfonylation, nitration, formylation, hydrolysis, and coupling procedures. These procedures are to introduce a functional group into the parent molecule (eg, nitration or sulfonylation of the aromatic ring) or to bond the two molecules together (eg, to bond the amine to a carboxylic acid). It can be used to obtain an amide; or to form a carbon-carbon bond between two heterocycles). For example, the alcohol or phenol group is in a solvent, eg, tetrahydrofuran, in the presence of phosphine (eg, triphenylphosphine) and a dehydrating agent (eg, diethyl azodicarboxylate, diisopropyl azodicarboxylate, or dimethyl azodicarboxylate). , Phenol can be converted to an ether group by binding with an alcohol. Alternatively, the ether group can be prepared by deprotonation of the alcohol with a suitable base (eg, sodium hydride) followed by the addition of an alkylating agent (eg, alkyl halide or alkyl sulfonate).

In another example, the primary or secondary amine can be alkylated using a reducing alkylation process. For example, amines, optionally in the presence of an acid (eg, acetic acid), in a solvent (eg, halogenated hydrocarbon, eg, dichloromethane, or alcohol, eg, ethanol), aldehyde and hydrogen borohydride (eg, ethanol). For example, it can be treated with sodium triacetoxyborohydride, or sodium cyanoborohydride).

In another example, the -OH group is the corresponding ester, acid, acid chloride by reduction with a suitable reducing agent, eg, complex metal hydride, eg lithium aluminum hydride, in a solvent (eg, tetrahydrofuran). Or it can be produced from aldehydes.

In another example, the hydroxy group (including the phenolic OH group) is a desorbing group, eg, a halogen atom or a sulfonyloxy group (eg, an alkylsulfonyloxy, eg, a trifluoro), using conditions known to those skilled in the art. It can be converted to methylsulfonyloxy, or arylsulfonyl, eg, p-toluenesulfonyloxy). For example, an aliphatic alcohol is reacted with thionyl chloride in a halogenated hydrocarbon (eg, dichloromethane) to give the corresponding alkyl chloride. Bases (eg, triethylamine) can also be used in this reaction.

In another example, the ester group can be converted to the corresponding carboxylic acid by acid- or base-catalyzed hydrolysis, depending on the nature of the ester group. Acid-catalyzed hydrolysis can be carried out by treatment with an organic or inorganic acid (eg, trifluoroacetic acid in an aqueous solvent, or a solvent, such as a mineral acid in a dioxane, such as hydrochloric acid). Base-catalyzed hydrolysis can be carried out by treatment with alkali metal hydroxides (eg, aqueous alcohols, eg lithium hydroxide in methanol).

In another example, the aromatic halogen substituent in the compound is a base (eg, a lithium base, eg, n-butyl) in a solvent (eg, tetrahydrofuran), optionally at a low temperature (eg, −78 ° C.). Alternatively, it may be subjected to a halogen-metal exchange by treatment with t-butyllithium), and the mixture can then be quenched with an electrophile to introduce the desired substituent. Thus, for example, a formyl group can be introduced using dimethylformamide as an electrophile. Aromatic halogen substituents can also be subjected to a palladium-catalyzed reaction to introduce a group such as a carboxylic acid, ester, cyano, or amino substituent.

In another example, the aromatic halogen substituent in the compound undergoes various metal-catalyzed reactions to introduce alternative functional groups such as amines, amides, ethers, thiols, aryl groups, or heteroaryl groups. Can be involved.

Specific oxidation methods include dehydrogenation and aromatization, and the addition of oxygen to specific functional groups. For example, the aldehyde group can be prepared by oxidation of the corresponding alcohol, using conditions well known to those skilled in the art. For example, alcohols can be treated with oxidizing agents (eg, Dess-Martin reagents) in solvents (eg, halogenated hydrocarbons, such as dichloromethane). Alternative oxidation conditions, such as treatment with oxalyl chloride and an activated amount of dimethyl sulfoxide, and subsequent quenching with the addition of amines (eg, triethylamine) can be used. Such a reaction is carried out in a suitable solvent (eg, a halogenated hydrocarbon, eg, dichloromethane) under suitable conditions (eg, below room temperature, eg, cooling to −78 ° C., followed by warming to room temperature). Can be done. In another example, the sulfur atom uses an oxidizing agent (eg, peroxyic acid, eg, 3-chloroperoxybenzoic acid) in an inert solvent (eg, halogenated hydrocarbon, eg, dichloromethane) at approximately ambient temperature. It can be used to oxidize to the corresponding sulfoxide or sulfone.

Specific reduction methods include the removal of oxygen atoms from specific functional groups and the saturation (or partial saturation) of unsaturated compounds containing aromatic rings. For example, a primary alcohol can be produced from the corresponding ester or aldehyde by reduction with a metal hydride (eg in solvent, eg lithium aluminum hydride or sodium borohydride). Alternatively, the -OH group can be produced from the corresponding carboxylic acid by reduction with a metal hydride (eg, lithium aluminum hydride in a solvent, eg, tetrahydrofuran). In another example, the nitro group is a catalytic hydrogen in a solvent (eg, ether, eg, tetrahydrofuran, or alcohol, eg, methanol) in the presence of a metal catalyst (eg, solid support, eg, palladium on carbon). It can be reduced to amines by conversion or by chemical reduction with a metal (eg, tin or iron) in the presence of an acid (eg, hydrochloric acid). In a further example, the amine is reduced by reduction of the nitrile, eg, in a solvent (eg, tetrahydrofuran), under suitable conditions (eg, below room temperature, eg, cooling to −78 ° C., or heating for reflux, eg). It is obtained by catalytic hydrogenation in the presence of a metal catalyst (eg, a solid support, eg, palladium on carbon), or Raney nickel.

Pharmaceutical Compositions The compounds used in the methods described herein are preferably in a biologically compatible form suitable for administration in vivo into pharmaceutical compositions for administration to human subjects. It is formulated. Pharmaceutical compositions typically include the compounds described herein and pharmaceutically acceptable excipients.

The compounds described herein can be used in the form of free bases, salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the present invention. Compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof can be administered to a patient in various forms, depending on the route of administration chosen, as will be appreciated by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, oral, sublingual, intranasal, rectal, patch, pump, or transdermal administration, pharmaceutical compositions. Is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical administration methods. Parenteral administration may be by continuous infusion over a selected period of time.

For use in humans, the compounds of the invention can be administered alone or in admixture with pharmaceutical carriers selected in connection with the intended route of administration and standard pharmaceutical practice. Here, the pharmaceutical composition for use according to the present invention processes a compound of the formula (I), (Ia), (Ib), (Va), or (Vb) into a preparation that can be used pharmaceutically. It can be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and auxiliaries that facilitate the use of the drug.

The present invention also includes pharmaceutical compositions that may contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or in the form of, for example, a capsule, sachet, paper, or other container. It is encapsulated in such a carrier. When the excipient acts as a diluent, it can be a vehicle, carrier or vehicle for the active ingredient, a solid, semi-solid, or liquid material (eg, saline). Thus, the composition can be in the form of tablets, powders, lozenges, sachets, cashiers, elixirs, suspensions, emulsions, liquids, syrups, as well as soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may include additional agents, such as preservatives.

Excipients or carriers are selected based on the method of administration and the route of administration. Suitable pharmaceutical carriers, as well as drug essentials for use in pharmaceutical formulations, are well-known references in the art, Remington: The Science and Practice of Pharmacy, 21 ^st Ed. , Gennaro, Ed. , Lippencott Williams & Wilkins (2005), and the USP / NF (United States Pharmacopeia and the National Formula). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup. , And methyl cellulose. Formulations include lubricants such as talc, magnesium stearate, and mineral oils; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. Further may be included. Other exemplary ^{excipients, Handbook of Pharmaceutical Excipients, 6 th} Edition, Rowe et al. , Eds. , Pharmaceutical Press (2009).

These pharmaceutical compositions are produced by conventional methods, for example, by conventional mixing, dissolving, granulating, dragee-making, trituration, emulsification, encapsulation, entrapping, or lyophilization processes. obtain. Well-known methods in the art for making formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed. , Gennaro, Ed. , Lippencott Williams & Wilkins (2005), and Energy dispedia of Pharmaceutical Technology, eds. J. Swerrick and J. C. Found in Boylan, 1988-1999, Marcel Dekker, New York. The appropriate formulation depends on the route of administration chosen. Formulations and preparations of such compositions are well known to those skilled in the art of pharmaceutical formulations. When preparing the formulation, the active compound can be ground to provide the proper particle size before combining with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, eg, about 40 mesh.

Dosage The dosage of a compound used in the methods described herein, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, depends on many factors, eg, the pharmacodynamic properties of the compound. It can vary depending on the method of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the frequency of treatment and the type of combination therapy, if any; and the clearance rate of the compound in the animal being treated. One of ordinary skill in the art can determine an appropriate dose based on the above factors. The compounds used in the methods described herein can be initially administered at a suitable dose that can be adjusted as needed, depending on the clinical response. In general, a preferred daily dose of a compound of the invention would be the amount of compound that is the lowest effective dose to produce a therapeutic effect. Such effective doses will generally depend on the factors mentioned above.

The compounds of the invention can be administered to a patient in single or multiple doses. When multiple doses are administered, the doses can be separated from each other by, for example, 1 to 24 hours, 1 to 7 days, 1 to 4 weeks, or 1 to 12 months. The compounds may be administered according to a schedule, or the compounds may be administered without a predetermined schedule. The active compound is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily, every 3 days, every 4 days, every 5 days, every other day. Or every 6 days, 1, 2, 3, 4, 5, 6, or 7 times a week, 1, 2, 3, 4, 5, or 6 times a month, or 1, 2, 3, 4, a year, It can be administered 5, 6, 7, 8, 9, 10, 11, or 12 times. For any specific subject, the specific dosing regimen should be adjusted over time according to the individual needs and the expert judgment of the person who administers or monitors the administration of the composition. It should be understood that there is.

Although the attending physician will ultimately determine the appropriate amount and dosing regimen, the effective amount of the compound of the invention is, for example, 0.05 mg to 3000 mg of any of the compounds described herein, eg, total. It can be a daily dose. Alternatively, the dose can be calculated using the patient's weight. Such a dose range may include, for example, 10 to 1000 mg (eg, 50 to 800 mg). In certain embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. To.

In the methods of the invention, the duration of administration of multiple doses of a compound of the invention to a patient can vary. For example, in certain embodiments, doses of the compounds of the invention are administered to the patient over a period of 1-7 days; 1-12 weeks; or 1-3 months. In other embodiments, the compound is administered to the patient over a period of, for example, 4-11 months or 1-30 years. In other embodiments, the compound is administered to the patient at the onset of symptoms. In any of these embodiments, the amount of compound administered can vary during the period of administration. When the compound is administered daily, administration may be performed, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily.

Formulations Compounds recognized to be able to treat any of the conditions described herein using any of the methods described herein are pharmaceutically acceptable in unit dosage forms. It can be administered to a patient or animal with a diluent, carrier, or excipient. Compounds for use in such treatments can be produced and isolated by any standard technique known to those skilled in the art of medicinal chemistry. Conventional pharmaceutical practices can be used to obtain formulations or compositions suitable for administering the identified compounds to patients suffering from necrotic diseases. Administration can be initiated before the patient exhibits symptoms.

An exemplary route of administration of a compound used in the present invention (eg, a compound of formula (I), (Ia), (Ib), (Va) or (Vb)) or a pharmaceutical composition thereof. Oral, sublingual, oral, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intrathecal, intraperitoneal, intranasal, inhalation, and topical. Including administration. The compound is preferably administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for the treatment of the diseases described herein are also part of the present invention.

Formulations for Oral Administration The pharmaceutical compositions envisioned by the present invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms are non-toxic, pharmaceutically acceptable excipients. The active ingredient may be contained in a mixture with the agent, eg, in the form of tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals. These excipients are, for example, inert. Diluters or fillers (eg, sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch with potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and Disintegrants (eg, cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, or alginic acid); binders (eg, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, Gelatin, starch, alpha starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol; and lubricants, lubricants, and anti-adhesion agents (eg,). Magnesium stearate, zinc stearate, stearic acid, silica, hydride vegetable oil, or talc). Other pharmaceutically acceptable excipients are colorants, flavoring agents, plasticizers, moisturizers, buffers. It can be an agent or the like.

Formulations for oral administration also include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (eg, potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or the active ingredient. Can be presented as chewable tablets, as soft gelatin capsules mixed with water or oil mediums, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pills can be prepared, for example, using a mixer, fluidized bed device or spray drying device, in a conventional manner, with the ingredients described above in tablets and capsules.

Controlled release compositions for oral use may be configured to release the effective drug by controlling the dissolution and / or diffusion of the effective drug substance. Any of several techniques can be performed to obtain controlled release and targeted plasma concentrations relative to the time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings. Examples include single or multiple units of tablet or capsule compositions, oils, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, the composition includes a biodegradable, pH, and / or temperature sensitive polymer coating.

Dissolution or diffusion controlled release can be achieved by the appropriate coating of the compound in tablets, capsules, pills, or granule formulations, or by incorporating the compound into the appropriate matrix. Controlled release coatings include the above coating materials and / or, for example, cellac, beeswax, glycowax, castor oil, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate. , Ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol It may contain one or more of methacrylates and / or polyethylene glycols. In controlled release matrix formulations, the matrix material is, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluoride. It may also contain carbonized carbon.

Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspending agents, and edible oils such as cottonseed oil, sesame oil, coconut oil. Emulsions flavored with oil or sesame oil, as well as elixirs and similar pharmaceutical vehicles.

Formulations for Oral Administration The dosage for oral or sublingual administration is typically 0.1-500 mg per single dose as needed. In practice, the physician will determine the actual dosing regimen that is most suitable for the individual patient, and the dose will vary with the age, weight, and response of the particular patient. The above doses are described for the average case, but there are individual cases in which higher or lower doses are advantageous, which are within the scope of the invention.

For oral administration, the composition may take the form of tablets, lozenges, etc. formulated by conventional methods. Liquid preparations suitable for use with atomizers and liquid sprayers and magnetohydrodynamic (EHD) aerosol devices typically include the compounds of the invention along with pharmaceutically acceptable carriers. Preferably, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol, or perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the compounds of the invention. Desirably, the material is a liquid, such as an alcohol, glycol, polyglycol, or fatty acid. Other methods of formulating liquid solutions or suspensions suitable for use in aerosol devices are known to those of skill in the art (eg, Biesalski's US Pat. No. 6, each incorporated herein by reference. (See 5,112,598 and Biesalski's US Pat. No. 5,556,611).

Formulations for Nasal or Inhaled Administration Compounds can also be formulated for nasal administration. Compositions for nasal administration can also be conveniently formulated as aerosols, drops, gels, and powders. The formulation may be provided in the form of single or multiple doses. In the case of droppers or pipettes, administration may be carried out by the patient administering a suitable volume of solution or suspension. In the case of spray, this can be done, for example, by a metered feed spray spray pump.

The compounds can also be formulated, in particular, for administration of aerosols to the respiratory tract by inhalation and intranasal administration. Compounds generally have a small particle size of, for example, about 5 μm or less. Such particle size is obtained by means known in the art, such as micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. Will be done. Aerosols may also conveniently contain surfactants such as lecithin. The dose of the drug can be controlled by a metered supply valve. Alternatively, the active ingredient is in the form of a dry powder, eg, a powder mixture of suitable powder bases, eg, lactose, starch, and starch derivatives, eg, hydroxypropyl methylcellulose, and compounds in polyvinylpyrrolidine (PVP). Can be provided at. The powder carrier becomes a gel in the nasal cavity. The powder composition may be provided in a unit dosage form, eg, in a capsule or cartridge, eg, a gelatin or blister pack, from which the powder can be administered by an inhaler.

Aerosol formulations typically include a solution or microsuspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and may usually take the form of a cartridge or refill for use with a sprayer. It is provided in sterile form in a sealed container in single or multiple doses. Alternatively, the sealed container can be a single distributor, eg, a single dose nasal inhaler or aerosol dispenser with a metering supply valve intended for disposal after use. If the dosage form comprises an aerosol dispenser, it contains a propellant, which can be a compressed gas, eg, compressed air or an organic propellant, eg, a fluorochlorohydrocarbon. Aerosol dosage forms can also take the form of pump atomizers.

Formulations for Parenteral Administration The compounds described herein for use in the methods of the invention are in the pharmaceutically acceptable parenteral (eg, intravenous or intramuscular) formulations described herein. Can be administered at. Pharmaceutical formulations may also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration are aqueous and non-aqueous sterile injections that may contain antioxidants, buffers, bacteriostatic agents and solutes that make the formulation isotonic with the blood of the recipient of interest; Also included are aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. For example, to prepare such compositions, the compounds of the invention can be dissolved or suspended in parenterally acceptable liquid vehicles. Among the acceptable vehicles and solvents that can be used, water, water adjusted to a suitable pH by the addition of water, an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic. There is a sodium chloride solution. Aqueous formulations may also contain one or more preservatives, such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate. Further information on parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formula (USP-NF), which is incorporated herein by reference.

Parenteral formulations can be any of the five common types of formulations identified by USP-NF as suitable for parenteral administration:
(1) "Drug Injection": a drug substance (eg, a compound of the formulas (I), (Ia), (Ib), (Va) or (Vb)), or a liquid preparation which is a solution thereof;
(2) “Drug for Injection”: a drug substance as a dry solid combined with a suitable sterile vehicle for parenteral administration as a drug injection (eg, formulas (I), (Ia), (Ib)). , (Va) or (Vb) compound);
(3) "Drug Injectable Emulsion": a drug substance dissolved or dispersed in a suitable emulsion medium (for example, formula (I), (Ia), (Ib), (Va) or (Vb)). Compound) liquid formulation;
(4) "Drug Injection Suspension": A drug substance suspended in a suitable liquid medium (eg, formula (I), (Ia), (Ib), (Va) or (Vb). ) Liquid formulation; and (5) "Drug for Injectable Suspension": a dry solid combined with a suitable sterile vehicle for parenteral administration as a drug injection suspension. Pharmaceutical substance (eg, a compound of formula (I), (Ia), (Ib), (Va) or (Vb)).

Exemplary formulations for parenteral administration include a solution of a surfactant, eg, a compound prepared in water, preferably mixed with hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, mixtures thereof with or without DMSO and alcohols, and oils. Under normal conditions of storage and use, these formulations may contain preservatives that prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed. , Gennaro, Ed. , Lippencott Williams & Wilkins (2005) and the United States Pharmacopeia (the National Formula) (USP 36 NF31) published in 2013.

Formulations for parenteral administration may contain, for example, excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, plant-derived oils, or hydrogenated naphthalene. A biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymer can be used to control the release of the compound. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. The inhalation formulation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Alternatively, it may be an oily solution for administration in the form of a nasal drop or as a gel.

Parenteral formulations can be formulated for immediate release or sustained release / sustained release of the compound. Exemplary formulations for parenteral release of compounds include aqueous solutions, powders for reconstruction, co-solvent solutions, oil / water emulsions, suspensions, oily solutions, liposomes, microspheres, and polymer gels.

Methods of Treatment The compounds and compositions described herein describe pathologies and diseases in which Hsp90 is involved, such as cell proliferative disorders such as cancer, neurodegenerative disorders such as tauopathy (eg Alzheimer's disease). , And can be used to treat infectious diseases.

Cell-proliferative disease Hsp90 has emerged as a major therapeutic target for cancer treatment due to the involvement of this multi-chaperone complex in various pathogenic cell processes. Hsp90 client proteins are acute myelogenous leukemia (Flt-3), breast cancer (HER2), chronic lymphocytic leukemia (Zap70), chronic myelogenous leukemia (Bcr-Abl or MBcr-Abl), gastrointestinal stromal tumor (c-). Kit), gastric cancer (c-Met), glioblastoma (mutated EGFR or c-Met), lung cancer (c-Met), lymphoma (NMP-ALK), melanoma (Raf-1 / mutant BRAF), Includes those involved in myelouma (IGF-1R / Akt), non-small cell lung cancer (mutant EGFR), kidney cancer, (HIF-1α), and small cell lung cancer (Akt). The compounds of the present invention are particularly useful in the treatment of brain tumors due to their blood-brain barrier penetrant properties. Brain tumors that can be treated with the compounds of the invention include gliomas or meningiomas, in particular glioblastomas (eg, glioblastomas) or neuroblastomas. Brain tumors (eg, brain tumors) that can be treated with the compounds of the invention according to the methods of the invention are primary tumors (tumors that develop in the brain) and metastatic tumors (tumors that develop in tissues other than brain tissue and metastasize to the brain). Tumor) may be included. Yet other cell proliferative disorders that can be treated by inhibition of Hsp90 are acute phase chronic myelogenous leukemia, leukemia, lymphoproliferative disorders, metastatic melanoma, multiple myeloma (eg, relapsed or refractory multiple myeloma). Tumors), myeloproliferative disorders, pancreatic cancers, small bowel cancers, and solid tumors. Furthermore, cancer cells have been shown to be more sensitive to Hsp90 inhibition than non-pathogenic cells. Therefore, the compounds described herein may be useful in the treatment of cell proliferative disorders.

Neurodegenerative Diseases Increased levels of Hsp90 are associated with neurodegenerative diseases. For example, abnormal Hsp90 activity has been demonstrated in tauopathy, a condition characterized by abnormal tau protein accumulation (eg, hyperphosphorylation and aggregated tau). Therefore, the compounds and compositions described herein include Alzheimer's disease (AD), silver granule disease, muscular atrophic lateral sclerosis, cerebral cortical basal nucleus degeneration, dementia pugi s listica, dementia. , Familial British dementia, frontotemporal degeneration (dementia without significant histopathological features), chronic traumatic encephalopathy, traumatic brain injury, frontotemporal dementia (FTD; eg, on chromosome 17) Frontotemporal dementia with linked Parkinson's disease (FTDP-17)), hippocampal tauopathy in brain aging, muscle tonic dystrophy type 1, Niemann-Pick's disease type C, Parkinson's disease (eg, Guam Parkinson's cognition) Useful for the treatment of neurodegenerative diseases and tauopathy, including complex disease, Parkinsonism with dementia of Guadeloop, or post-encephalitis Parkinson's disease, Pick's disease (PiD), and advanced nuclear paralysis. possible. Therefore, the compounds described herein may be useful in treating neurodegenerative diseases such as tauopathy (eg Alzheimer's disease).

Infectious diseases Hsp90 has emerged as a therapeutic target for treating infectious diseases such as viral, fungal, and bacterial infections. Many pathogens (eg, viruses, fungi, and bacteria) rely on Hsp90-dependent processes (eg, Geller et al., Biochim. Biophyss. Acta-Mol. Cell Res., 1823: 698-706). , 2012; the entire disclosure of which is incorporated herein by reference). Therefore, inhibition of Hsp90 has a therapeutic effect on patients suffering from infections that depend on the activity of Hsp90. For example, an Hsp90 inhibitor (gerdanamycin) has been shown to slow the growth of influenza virus in cell cultures. Other viruses that depend on the Hsp90-dependent process include those belonging to the following families: Herpesviridae (eg, simple herpesvirus type 1, simple herpesvirus type 2, herpes herpesvirus type 5). , Kaposi sarcoma-related herpes virus, varicella herpes virus, or Epstein bar virus), Polyomaviridae (eg, SV40), Poxviridae (eg, vaccinia virus), Leoviridae ) (For example, Rotavirus), Birnaviridae (for example, infectious Fabricius cyst virus), Picornaviridae (for example, poliovirus, rhinovirus, or coxsackie virus), flavivirus (eg,) Flaviviridae (eg, hepatitis C virus or dengue virus), Arenaviridae (eg, lymphocytic choriomyelitis virus), Hepeviridae (eg, hepatitis E virus), Rabdovirus (eg, hepatitis E virus) Rhabdoviridae (eg, bullous stomatitis virus), Paramixyviridae (eg, human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus), Bunyavirus family (eg, human parainfluenza virus type 2) Bunyaviridae (eg, Lacrosvirus), Orthomoxyviridae (eg, influenza A virus), Firoviridae (eg, Ebolavirus), Retroviridae (eg, HTLV1) or HTLV1 ), And Hepadnaviridae (eg, hepatitis B virus). Hsp90 inhibitors are also used in the treatment of fungal infections, such as Candida albicans, Aspergillus fumigates, or Pneumocystis jirovec in vivo. In addition, Hsp90 inhibitors are also useful in the treatment of bacterial infections such as acid-fast bacilli, anthrax, or bacterial pneumonia. A description of the diseases that can be treated with Hsp90 inhibitors is set forth in US Patent Application Publication No. 2011/01/201587, the entire disclosure of which is incorporated herein by reference. Therefore, the compounds of the present invention can be used to treat infectious diseases, such as viral, fungal, or bacterial infections, according to the methods of the invention.

Inflammatory and autoimmune diseases, allergies Hsp90 has been shown to play a role in antigen presentation, lymphocyte and macrophage activation, dendritic cell maturation, and induction of enhanceosome-mediated inflammation. Hsp90 inhibition is associated with blockade of inflammatory components, such as reduced cytokine and NO production, and blockade of NFκB translocation. In addition, considerable studies have shown that chaperones such as Hsp90 induce the production of anti-inflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells via the TLR2- and 4-signal transduction pathways. Show that it is possible. Therefore, Hsp90 appears to be able to act as a potent activator of the innate immune system. In fact, high levels of Hsp90 were detected in the sera of patients with systemic lupus erythematosus. Hsp-reactive autoantibodies and cells were detected in patients with rheumatoid arthritis. It was also observed that the anti-inflammatory effect of inhibiting Hsp90 reduced airway inflammation in a mouse model of asthma. The compounds of the present invention may be applicable in the treatment of inflammatory or autoimmune diseases in patients. In addition, the anti-inflammatory effect of Hsp90 inhibition may have therapeutic uses in the treatment of allergies. Therefore, the compounds of the present invention can be used in the treatment of allergies.

Cardiovascular disease Hsp90 has recently been implicated in the etiology of cardiovascular diseases such as atherosclerosis and cardiomyopathy. Therefore, the compounds of the present invention may be applicable for the treatment of cardiovascular diseases (eg, atherosclerosis or cardiomyopathy).

Kits of the Invention The present invention relates to (i) the pharmaceutical compositions of the present invention and (ii) mammalian diseases caused by the action of Hsp90, eg, neurodegenerative diseases, proliferation, as described herein. A kit containing instructions for use of the pharmaceutical composition for treating a sexual or infectious disease is also provided. The kit of the present invention may include instructions describing how a practitioner (eg, a doctor, nurse, caregiver, or patient) may administer the compositions contained in the kit. The pharmaceutical compositions in the kits of the invention can be provided in containers (eg, bottles, ampoules, tubes, or blister packs). In addition, the kit includes additional components, such as instructions or dosing schedules for patients suffering from neurodegenerative or proliferative disorders, and optionally a device for administering the pharmaceutical composition (eg, eg). , Syringe) can also be included.

The following examples are intended to illustrate the present invention. The examples are by no means intended to limit the invention.

スキーム１．試薬および条件：（ａ）Ｐｄ（ＰＰｈ₃）₄、Ｎａ₂ＣＯ₃、ジオキサン／Ｈ₂Ｏ（９／５）、９０℃、７２％。
４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０）。５，７−ジクロロ−２，３−ジヒドロ−１−ベンゾフラン−４−イルボロン酸（２３３ｍｇ、１．０ｍｍｏｌ）と、４−クロロ−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２１９ｍｇ、１．３ｍｍｏｌ）と、炭酸ナトリウム（３１８ｍｇ、３．０ｍｍｏｌ）と、パラジウムテトラキス（トリフェニルホスフィン）と、ジオキサン／水（９／５、１４ｍｌ）との混合物を、２０時間にわたってアルゴン下で、９０℃で撹拌し、次に、室温に冷まし、塩水（２５ｍｌ）でクエンチし、酢酸エチル（３０ｍｌ×２）で抽出した。組み合わされた有機層を硫酸ナトリウム上で乾燥させ、濃縮した。残渣を、シクロヘキサン／酢酸エチル（１００／０〜３０／７０、１５分）を用いてシリカゲルにおけるクロマトグラフィーによって精製したところ、生成物が白色の固体（２３０ｍｇ、７２％）として得られた。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ８．０１（ｓ，１Ｈ）、７．４５（ｔ，Ｊ＝３Ｈｚ、１Ｈ）、７．３４（ｓ，１Ｈ）、６．４６（ｍ，１Ｈ）、４．８３（ｓ，２Ｈ）、４．７１（ｍ，２Ｈ）、３．６０（ｍ，１Ｈ）、２．９４（ｍ，１Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３２１．０（［Ｃ₁₄Ｈ₁₀Ｃｌ₂Ｎ₄Ｏ＋Ｈ］⁺に対する計算値：３２１．０）． Example 1. Synthesis of compounds of the present invention

Scheme 1. Reagents and conditions: (a) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ , dioxane / H ₂ O (9/5), 90 ° C., 72%.
4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (20). 5,7-Dichloro-2,3-dihydro-1-benzofuran-4-ylboronic acid (233 mg, 1.0 mmol) and 4-chloro-5H-pyrrolo [3,2-d] pyrimidin-2-amine (219 mg) , 1.3 mmol), sodium carbonate (318 mg, 3.0 mmol), palladium tetrakis (triphenylphosphine) and dichloromethane / water (9/5, 14 ml) over 90 hours under argon. The mixture was stirred at ° C., then cooled to room temperature, quenched with salt water (25 ml) and extracted with ethyl acetate (30 ml × 2). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel with cyclohexane / ethyl acetate (100 / 0-30 / 70, 15 min) to give the product as a white solid (230 mg, 72%). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.45 (t, J = 3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H) 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M + H] ⁺ : 321.0 ([C _14] Calculated value for H ₁₀ Cl ₂ N ₄ O + H] ⁺ : 321.0).

The following compounds of the invention were prepared according to the procedures described herein.

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ，６−ジメチルピリミジン−２−アミン（３）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２５（ｓ，１Ｈ）、６．５７（ｓ，１Ｈ）、５．０７（ｄ，Ｊ＝１０Ｈｚ、１Ｈ）、４．６８（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２９（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．０２（ｄ，Ｊ＝１０Ｈｚ、３Ｈ）、２．４０（ｓ，３Ｈ）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N, 6-dimethylpyrimidine-2-amine (3). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 6.57 (s, 1H), 5.07 (d, J = 10 Hz, 1H), 4.68 (t, J = 9Hz, 2H), 3.29 (t, J = 9Hz, 2H), 3.02 (d, J = 10Hz, 3H), 2.40 (s, 3H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ，Ｎ，６−トリメチルピリミジン−２−アミン（４）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２５（ｓ，１Ｈ）、６．５１（ｓ，１Ｈ）、４．６７（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．３０（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２０（ｓ，６Ｈ）、２．４０（ｓ，３Ｈ）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N, N, 6-trimethylpyrimidine-2-amine (4). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 6.51 (s, 1H), 4.67 (t, J = 9 Hz, 2H), 3.30 (t, J = 9Hz, 2H), 3.20 (s, 6H), 2.40 (s, 3H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−６−メチルピリミジン−２−アミン（５）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２７（ｓ，１Ｈ）、６．６４（ｓ，１Ｈ）、５．０４（ｓ，２Ｈ）、４．６８（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２５（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、２．４２（ｓ，３Ｈ）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -6-methylpyrimidine-2-amine (5). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 6.64 (s, 1H), 5.04 (s, 2H), 4.68 (t, J = 9Hz, 2H) 3.25 (t, J = 9Hz, 2H), 2.42 (s, 3H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−６−エチルピリミジン−２−アミン（６）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２７（ｓ，１Ｈ）、６．６５（ｓ，１Ｈ）、５．０５（ｓ，２Ｈ）、４．６８（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２６（ｔ，Ｊ＝８．５Ｈｚ、２Ｈ）、２．６８（ｑ，Ｊ＝８Ｈｚ、２Ｈ）、１．２９（ｔ，Ｊ＝７．５Ｈｚ、３Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３１０．１（［Ｃ１４Ｈ１３Ｃｌ２Ｎ３Ｏ＋Ｈ］⁺に対する計算値：３１０．０４）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -6-ethylpyrimidine-2-amine (6). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 6.65 (s, 1H), 5.05 (s, 2H), 4.68 (t, J = 9Hz, 2H) 3.26 (t, J = 8.5Hz, 2H), 2.68 (q, J = 8Hz, 2H), 1.29 (t, J = 7.5Hz, 3H); LCMS [M + H] ⁺ : 310.1 (calculated value for [C14H13Cl2N3O + H] ⁺ : 310.04).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−６−イソプロピルピリミジン−２−アミン（７）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２８（ｓ，１Ｈ）、６．６６（ｓ，１Ｈ）、５．０４（ｓ，２Ｈ）、４．６９（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２７（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、２．８７（ｍ，１Ｈ）、１．２８（ｄ，Ｊ＝７Ｈｚ、６Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３２４．０２（［Ｃ１５Ｈ１５Ｃｌ２Ｎ３Ｏ＋Ｈ］⁺に対する計算値：３２４．０６）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -6-isopropylpyrimidine-2-amine (7). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 6.66 (s, 1H), 5.04 (s, 2H), 4.69 (t, J = 9Hz, 2H) 3.27 (t, J = 9Hz, 2H), 2.87 (m, 1H), 1.28 (d, J = 7Hz, 6H); LCMS [M + H] ⁺ : 324.02 ([C15H15Cl2N3O + H] ⁺ Calculated value for: 324.06).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−６−メトキシピリミジン−２−アミン（８）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２８（ｓ，１Ｈ）、６．１９（ｓ，１Ｈ）、４．９８（ｓ，２Ｈ）、４．６８（ｔ，Ｊ＝８．５Ｈｚ、２Ｈ）、３．９４（ｓ，３Ｈ）、３．２５（ｔ，Ｊ＝９Ｈｚ、２Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３１１．８７（［Ｃ１３Ｈ１１Ｃｌ２Ｎ３Ｏ２＋Ｈ］⁺に対する計算値：３１２．０２）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -6-methoxypyrimidine-2-amine (8). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 6.19 (s, 1H), 4.98 (s, 2H), 4.68 (t, J = 8.5 Hz, 2H), 3.94 (s, 3H), 3.25 (t, J = 9Hz, 2H); LCMS [M + H] ⁺ : 311.87 (calculated value for [C13H11Cl2N3O2 + H] ⁺ : 312.02).

４−（２，４−ジクロロ−５−メトキシフェニル）−５，６−ジメチルピリミジン−２−アミン（９）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．４７（ｓ，１Ｈ）、６．８３（ｓ，１Ｈ）、４．８８（ｓ，２Ｈ）、３．９０（ｓ，３Ｈ）、２．４２（ｓ，３Ｈ）、１．９５（ｓ，３Ｈ）．

4- (2,4-dichloro-5-methoxyphenyl) -5,6-dimethylpyrimidine-2-amine (9). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.90 (s, 3H), 2.42 (S, 3H), 1.95 (s, 3H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５，６−ジメチルピリミジン−２−アミン（１０）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２５（ｓ，１Ｈ）、４．８９（ｓ，２Ｈ）、４．６９（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２５（ｍ，１Ｈ）、２．８８（ｍ，１Ｈ）、２．４２（ｓ，３Ｈ）、１．９３（ｓ，３Ｈ）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5,6-dimethylpyrimidine-2-amine (10). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 4.89 (s, 2H), 4.69 (t, J = 9 Hz, 2H), 3.25 (m, 1H) 2.88 (m, 1H), 2.42 (s, 3H), 1.93 (s, 3H).

４−（２−クロロ−４−フルオロ−５−メトキシフェニル）−６，７−ジヒドロ−５Ｈ−シクロペンタ［ｄ］ピリミジン−２−アミン（１１）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２０（ｄ，Ｊ＝１０．５Ｈｚ、１Ｈ）、６．９４（ｄ，Ｊ＝９Ｈｚ、１Ｈ）、４．９９（ｓ，２Ｈ）、３．９０（ｓ，３Ｈ）、２．９１（ｔ，Ｊ＝８Ｈｚ、２Ｈ）、２．７２（ｔ，Ｊ＝７．５Ｈｚ、２Ｈ）、２．０８（ｍ，２Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：２９４．２（［Ｃ１４Ｈ１３ＣｌＦＮ３Ｏ＋Ｈ］⁺に対する計算値：２９４．０７）．

4- (2-Chloro-4-fluoro-5-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidine-2-amine (11). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.20 (d, J = 10.5 Hz, 1H), 6.94 (d, J = 9 Hz, 1H), 4.99 (s, 2H), 3. 90 (s, 3H), 2.91 (t, J = 8Hz, 2H), 2.72 (t, J = 7.5Hz, 2H), 2.08 (m, 2H); LCMS [M + H] ⁺ : 294.2 (calculated value for [C14H13ClFN3O + H] ⁺ : 294.07).

４−（２，４−ジクロロ−５−メトキシフェニル）−６，７−ジヒドロ−５Ｈ−シクロペンタ［ｄ］ピリミジン−２−アミン（１２）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．４７（ｓ，１Ｈ）、６．９０（ｓ，１Ｈ）、４．９８（ｓ，２Ｈ）、３．９１（ｓ，３Ｈ）、２．９２（ｔ，Ｊ＝７．５Ｈｚ、２Ｈ）、２．７２（ｔ，Ｊ＝７．５Ｈｚ、２Ｈ）、２．０８（ｍ，２Ｈ）．

4- (2,4-dichloro-5-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidine-2-amine (12). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 6.90 (s, 1H), 4.98 (s, 2H), 3.91 (s, 3H), 2.92 (T, J = 7.5Hz, 2H), 2.72 (t, J = 7.5Hz, 2H), 2.08 (m, 2H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−６，７−ジヒドロ−５Ｈ−シクロペンタ［ｄ］ピリミジン−２−アミン（１３）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２５（ｓ，１Ｈ）、４．６９（ｍ，２Ｈ）、３．３８（ｍ，１Ｈ）、２．９９−２．８１（ｍ，４Ｈ）、２．４９（ｍ，１Ｈ）、２．１７−２．００（ｍ，２Ｈ）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -6,7-dihydro-5H-cyclopenta [d] pyrimidine-2-amine (13). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.25 (s, 1H), 4.69 (m, 2H), 3.38 (m, 1H), 2.99-2.81 (m, 4H) 2.49 (m, 1H), 2.17-2.00 (m, 2H).

４−（２，４−ジクロロ−５−（２−（ジメチルアミノ）エトキシ）フェニル）−６，７−ジヒドロ−５Ｈ−シクロペンタ［ｄ］ピリミジン−２−アミン（１４）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．４６（ｓ，１Ｈ）、６．９０（ｓ，１Ｈ）、４．９７（ｓ，２Ｈ）、４．１３（ｔ，Ｊ＝６Ｈｚ、２Ｈ）、２．９１（ｔ，Ｊ＝８Ｈｚ、２Ｈ）、２．８０（ｔ，Ｊ＝６Ｈｚ、２Ｈ），２．７１（ｔ，Ｊ＝７．５Ｈｚ、２Ｈ）、２．３６（ｓ，６Ｈ）、２．０８（ｍ，２Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３６７．１（［Ｃ１７Ｈ２０Ｃｌ２Ｎ４Ｏ＋Ｈ］⁺に対する計算値：３６７．１０）．

4- (2,4-dichloro-5-(2- (dimethylamino) ethoxy) phenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine (14). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.46 (s, 1H), 6.90 (s, 1H), 4.97 (s, 2H), 4.13 (t, J = 6Hz, 2H) 2.91 (t, J = 8Hz, 2H), 2.80 (t, J = 6Hz, 2H), 2.71 (t, J = 7.5Hz, 2H), 2.36 (s, 6H) , 2.08 (m, 2H); LCMS [M + H] ⁺ : 367.1 (calculated value for [C17H20Cl2N4O + H] ⁺ : 367.10).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５，６，７，８−テトラヒドロキサゾリン−２−アミン（１５）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．２８（ｓ，１Ｈ）、４．８８（ｓ，２Ｈ）、４．６９（ｔ，Ｊ＝９Ｈｚ、２Ｈ）、３．２１（ｍ，１Ｈ）、２．８９（ｍ，１Ｈ）、２．７８（ｍ，２Ｈ）、２．４４（ｍ，１Ｈ）、２．１５（ｍ，１Ｈ）、１．８６（ｍ，２Ｈ）、１．７２（ｍ，２Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３３６．１（［Ｃ１６Ｈ１５Ｃｌ２Ｎ３Ｏ＋Ｈ］⁺に対する計算値：３３６．０６）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5,6,7,8-tetrahydroxazoline-2-amine (15). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 4.88 (s, 2H), 4.69 (t, J = 9Hz, 2H), 3.21 (m, 1H) 2.89 (m, 1H), 2.78 (m, 2H), 2.44 (m, 1H), 2.15 (m, 1H), 1.86 (m, 2H), 1.72 ( m, 2H); LCMS [M + H] ⁺ : 336.1 (calculated value for [C16H15Cl2N3O + H] ⁺ : 336.06).

４−（２，４−ジクロロ−５−メトキシフェニル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（１９）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ８．１５（ｓ，１Ｈ）、７．５４（ｓ，１Ｈ）、７．４６（ｍ，１Ｈ）、７．１５（ｓ，１Ｈ）、６．４５（ｍ，１Ｈ）、４．８６（ｓ，２Ｈ）、３．９４（ｓ，３Ｈ）．

4- (2,4-dichloro-5-methoxyphenyl) -5H-pyrrolo [3,2-d] pyrimidine-2-amine (19). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 8.15 (s, 1H), 7.54 (s, 1H), 7.46 (m, 1H), 7.15 (s, 1H), 6.45 (M, 1H), 4.86 (s, 2H), 3.94 (s, 3H).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ８．０１（ｓ，１Ｈ）、７．４５（ｔ，Ｊ＝３Ｈｚ、１Ｈ）、７．３４（ｓ，１Ｈ）、６．４６（ｍ，１Ｈ）、４．８３（ｓ，２Ｈ）、４．７１（ｍ，２Ｈ）、３．６０（ｍ，１Ｈ）、２．９４（ｍ，１Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３２１．０（［Ｃ₁₄Ｈ₁₀Ｃｌ₂Ｎ₄Ｏ＋Ｈ］⁺に対する計算値：３２１．０）．¹Ｈ ＮＭＲスペクトルが、図１に示される。

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (20). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.45 (t, J = 3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H) 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M + H] ⁺ : 321.0 ([C _14] Calculated value for H ₁₀ Cl ₂ N ₄ O + H] ⁺ : 321.0). ^{The 1 1} H NMR spectrum is shown in FIG.

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５−メチル−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２１）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．３２（ｓ，１Ｈ）、７．２２（ｄ，Ｊ＝３Ｈｚ、１Ｈ）、６．３６（ｄ，Ｊ＝３Ｈｚ、１Ｈ）、４．８１（ｓ，２Ｈ）、４．７２（ｍ，２Ｈ）、３．４０（ｓ，３Ｈ）、３．３４（ｍ，１Ｈ）、２．９１（ｍ，１Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３３５．０（［Ｃ１５Ｈ１２Ｃｌ２Ｎ４Ｏ＋Ｈ］⁺に対する計算値：３３５．０４）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5-methyl-5H-pyrrolo [3,2-d] pyrimidin-2-amine (21). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.32 (s, 1H), 7.22 (d, J = 3 Hz, 1H), 6.36 (d, J = 3 Hz, 1H), 4.81 ( s, 2H), 4.72 (m, 2H), 3.40 (s, 3H), 3.34 (m, 1H), 2.91 (m, 1H); LCMS [M + H] ⁺ : 335.0 (Calculated value for [C15H12Cl2N4O + H] ⁺ : 335.04).

４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５−エチル−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２２）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．３３（ｍ，２Ｈ）、６．４０（ｄ，Ｊ＝２．５Ｈｚ、１Ｈ）、４．８０（ｓ，２Ｈ）、４．７０（ｍ，２Ｈ）、３．７２（ｄ，Ｊ＝７Ｈｚ、２Ｈ）、３．３３（ｍ，１Ｈ）、２．９１（ｍ，１Ｈ）、１．１４（ｔ，Ｊ＝７．５Ｈｚ、３Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：３４９．１（［Ｃ１６Ｈ１４Ｃｌ２Ｎ４Ｏ＋Ｈ］⁺に対する計算値：３４９．０５）．

4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5-ethyl-5H-pyrrolo [3,2-d] pyrimidin-2-amine (22). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.33 (m, 2H), 6.40 (d, J = 2.5 Hz, 1H), 4.80 (s, 2H), 4.70 (m, 2H), 3.72 (d, J = 7Hz, 2H), 3.33 (m, 1H), 2.91 (m, 1H), 1.14 (t, J = 7.5Hz, 3H); LCMS [M + H] ⁺ : 349.1 (calculated value for [C16H14Cl2N4O + H] ⁺ : 349.05).

エチル−２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキシレート（２３）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．５４（ｓ，１Ｈ）、７．３５（ｓ，１Ｈ）、５．３２（ｓ，２Ｈ）、４．７０（ｍ，２Ｈ）、４．３７（ｍ，２Ｈ）、３．３５（ｍ，１Ｈ）、２．９２（ｍ，１Ｈ）、１．３８（ｔ，Ｊ＝７Ｈｚ、３Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：４１０．０（［Ｃ１７Ｈ１３Ｃｌ２Ｎ３Ｏ３Ｓ＋Ｈ］⁺に対する計算値：４１０．０１）．

Ethyl-2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxylate (23). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.54 (s, 1H), 7.35 (s, 1H), 5.32 (s, 2H), 4.70 (m, 2H), 4.37 (M, 2H), 3.35 (m, 1H), 2.92 (m, 1H), 1.38 (t, J = 7Hz, 3H); LCMS [M + H] ⁺ : 410.0 ([C17H13Cl2N3O3S + H] Calculated value for ⁺ : 410.01).

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−エチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（２４）。¹Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ₃）：δ ７．３４（ｓ，１Ｈ）、７．２１（ｓ，１Ｈ）、５．９１（ｓ，１Ｈ）、５．２８（ｓ，２Ｈ）、４．７０（ｍ，２Ｈ）、４．４８（ｍ，２Ｈ）、３．３６（ｍ，１Ｈ）、２．９１（ｍ，１Ｈ）、１．２６（ｔ，Ｊ＝３．５Ｈｚ、３Ｈ）；ＬＣＭＳ［Ｍ＋Ｈ］⁺：４０９．０（［Ｃ１７Ｈ１４Ｃｌ２Ｎ４Ｏ２Ｓ＋Ｈ］⁺に対する計算値：４０９．０２）．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-ethylthieno [2,3-d] pyrimidine-6-carboxamide (24). ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ 7.34 (s, 1H), 7.21 (s, 1H), 5.91 (s, 1H), 5.28 (s, 2H), 4.70 (M, 2H), 4.48 (m, 2H), 3.36 (m, 1H), 2.91 (m, 1H), 1.26 (t, J = 3.5Hz, 3H); LCMS [ M + H] ⁺ : 409.0 (calculated value for [C17H14Cl2N4O2S + H] ⁺ : 409.02).

Compounds 34 and 36 were prepared according to methods known in the art, such as those described herein. ^{1 1} H NMR spectra (CDCl ₃ ) for compounds 34 and 36 are shown in FIGS. 2 and 3, respectively.

Compounds 40-48 can be prepared according to methods known in the art, such as those described herein.

４−クロロ−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−２−アミン（４９）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．４８（ｓ，１Ｈ）、７．３０（ｓ，２Ｈ）、６．７８（ｓ，１Ｈ）、４．６４（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２０（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）．ＬＣＭＳ：ｍ／ｚ Ｃ₁₂Ｈ₈Ｃｌ₃Ｎ₃Ｏ［Ｍ＋Ｈ］⁺に対する計算値：３１６．０；実測値：３１６．０．

4-Chloro-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidin-2-amine (49). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.48 (s, 1H), 7.30 (s, 2H), 6.78 (s, 1H), 4.64 (t, J = 8. 8Hz, 2H), 3.20 (t, J = 8.8Hz, 2H). LCMS: calculated value for m / z C ₁₂ H ₈ Cl ₃ N ₃ O [M + H] ⁺ : 316.0; measured value: 316.0.

４−トリフルオロメチル−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−２−アミン（５０）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ ７．５２０（ｂｒ ｓ，２Ｈ、ＮＨ₂）、７．０９３（ｓ，１Ｈ）、４．６５５（ｔ，２Ｈ、Ｊ＝８．８Ｈｚ）、３．５４７（ｓ，１Ｈ）、３．２２１（ｔ，２Ｈ、Ｊ＝８．８Ｈｚ）．ＬＣＭＳ：ｍ／ｚ Ｃ₁₃Ｈ₈Ｃｌ₂Ｆ₃Ｎ₃Ｏ［Ｍ＋Ｈ］⁺に対する計算値：３５０．１；実測値：３５０．０．

4-Trifluoromethyl-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidin-2-amine (50). ^{1 1} H NMR (400 MHz, DMSO-d6): δ 7.520 (br s, 2H, NH ₂ ), 7.093 (s, 1H), 4.655 (t, 2H, J = 8.8 Hz), 3 .547 (s, 1H), 3.221 (t, 2H, J = 8.8Hz). LCMS: calculated value for m / z C ₁₃ H ₈ Cl ₂ F ₃ N ₃ O [M + H] ⁺ : 350.1; measured value: 350.0.

４−チオメチル−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−２−アミン（５１）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ ７．４３８（ｓ，１Ｈ）、６．８１５（ｂｒ ｓ，２Ｈ、ＮＨ₂）、６．５４９（ｓ，１Ｈ）、４．６３３（ｔ，２Ｈ、Ｊ＝８．８Ｈｚ）、３．１７８（ｔ，２Ｈ、Ｊ＝８．８Ｈｚ）、２．４５３（ｓ，３Ｈ）．ＬＣＭＳ：ｍ／ｚ Ｃ₁₃Ｈ₁₁Ｃｌ₂Ｎ₃ＯＳ［Ｍ＋Ｈ］⁺に対する計算値：３２８．２；実測値：３２８．１．

4-Thiomethyl-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidin-2-amine (51). ^{1 1} H NMR (400 MHz, DMSO-d6): δ 7.438 (s, 1H), 6.815 (br s, 2H, NH ₂ ), 6.549 (s, 1H), 4.633 (t, 2H) , J = 8.8 Hz), 3.178 (t, 2H, J = 8.8 Hz), 2.453 (s, 3H). LCMS: m / z C ₁₃ H ₁₁ Cl ₂ N ₃ OS [M + H] ⁺ Calculated value: 328.2; Measured value: 328.1.

４−クロロ−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−２，５−ジアミン（５２）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．４６（ｓ，１Ｈ）、６．２５（ｓ，２Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、４．３０（ｓ，２Ｈ）、３．１５−３．０７ ｍ、２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₂Ｈ₉Ｃｌ₃Ｎ₄Ｏ［Ｍ＋Ｈ］⁺に対する計算値：３３１．０；実測値：３３１．１．

4-Chloro-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidine-2,5-diamine (52). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.46 (s, 1H), 6.25 (s, 2H), 4.67 (t, J = 8.8 Hz, 2H), 4.30 ( s, 2H) 3.15-3.07 m, 2H). HPLC / MS: m / z C ₁₂ H ₉ Cl ₃ N ₄ O [M + H] ⁺ Calculated value: 331.0; Measured value: 331.1.

２−アミノ−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−４−オール（５３）。ジオキサン：１ＮのＮａＯＨ水溶液（５０：５０；１ｍＬ：１ｍＬ）を含むフラスコに、４−クロロ−６−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ピリミジン−２−アミン（４９）（２０ｍｇ、０．０６３ｍｍｏｌ）、およびＤＡＢＣＯ（８ｍｇ、０．０６９ｍｍｏｌ）を室温で加えた。続いて、反応物を８０℃で加熱した。反応物を冷まし、１ＮのＨＣｌ水溶液（２ｍＬ）の添加によって酸性化し、酢酸エチル（５ｍＬ）に取り込み、塩水（３×５ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、白色の固体として７７％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．３９（ｓ，１Ｈ）、５．５７（ｓ，１Ｈ）、４．６２（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２０（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₂Ｈ₉Ｃｌ₂Ｎ₃Ｏ₂［Ｍ＋Ｈ］⁺に対する計算値：２９８．０；実測値：２９８．１．

2-Amino-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidin-4-ol (53). 4-Chloro-6- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) pyrimidin-2-amine (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) in a flask containing a 1N aqueous NaOH solution (50:50; 1 mL: 1 mL). 49) (20 mg, 0.063 mmol) and DABCO (8 mg, 0.069 mmol) were added at room temperature. Subsequently, the reaction was heated at 80 ° C. The reaction was cooled, acidified by the addition of 1N aqueous HCl (2 mL), incorporated into ethyl acetate (5 mL) and washed with brine (3 x 5 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a white solid in 77% yield.
^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.39 (s, 1H), 5.57 (s, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.20 ( t, J = 8.8Hz, 2H). HPLC / MS: m / z C ₁₂ H ₉ Cl ₂ N ₃ O ₂ [M + H] ⁺ Calculated value: 298.0; Measured value: 298.1.

メチル２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−５−カルボキシレート（５４）。ＤＣＭ（１ｍＬ）中の４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０）（２０ｍｇ、０．０６２ｍｍｏｌ）を含むフラスコに、乾燥Ｋ₂ＣＯ₃（３０ｍｇ、０．２２ｍｍｏｌ）、およびクロロギ酸メチル（０．０１４ｍＬ、０．１８６ｍｍｏｌ）を０℃で加えた。反応物を室温で８時間撹拌させた。その後、反応物を、１ＮのＮａＯＨ水溶液（１ｍＬ）の添加によってクエンチし、室温で１時間撹拌した。反応物をＤＣＭ（１０ｍＬ）に取り込み、飽和ＮａＨＣＯ₃水溶液（１０ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、黄色の固体として６６％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）：δ＝７．６１（ｓ，１Ｈ）、７．２３（ｓ，１Ｈ）、６．５１（ｓ，１Ｈ）、４．６３（ｂｒ ｓ，２Ｈ）、３．７７（ｓ，３Ｈ）、３．６５（ｂｒ ｓ，１Ｈ）、２．８５（ｂｒ ｓ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₆Ｈ₁₂Ｃｌ₂Ｎ₄Ｏ₃［Ｍ＋Ｈ］⁺に対する計算値：３７９．０；実測値：３７９．１．

Methyl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidine-5-carboxylate (54). 4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (20) in DCM (1 mL) (20 mg, 0. To a flask containing (062 mmol) was added dry K ₂ CO ₃ (30 mg, 0.22 mmol) and methyl chloroformate (0.014 mL, 0.186 mmol) at 0 ° C. The reaction was stirred at room temperature for 8 hours. The reaction was then quenched by the addition of 1N aqueous NaOH solution (1 mL) and stirred at room temperature for 1 hour. The reaction was taken up in DCM (10 mL) and washed with saturated aqueous NaHCO ₃ solution (10 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a yellow solid in 66% yield.
^{1 1} H NMR (400 MHz, CDCl3): δ = 7.61 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 4.63 (br s, 2H), 3. 77 (s, 3H), 3.65 (br s, 1H), 2.85 (br s, 1H). HPLC / MS: m / z C ₁₆ H ₁₂ Cl ₂ N ₄ O ₃ [M + H] ⁺ Calculated value: 379.0; Measured value: 379.1.

１−（２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−５−イル）エタン−１−オン（５５）。ＤＣＭ（１ｍＬ）中の４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０ｍｇ、０．０６２ｍｍｏｌ）を含むフラスコに、乾燥Ｋ₂ＣＯ₃（３０ｍｇ、０．２２ｍｍｏｌ）、および塩化アセチル（０．００６ｍＬ、０．０７４ｍｍｏｌ）を０℃で加えた。反応物を室温で８時間撹拌させた。その後、反応物を、１ＮのＮａＯＨ水溶液（１ｍＬ）の添加によってクエンチし、室温で１時間撹拌した。反応物をＤＣＭ（１０ｍＬ）に取り込み、飽和ＮａＨＣＯ₃水溶液（１０ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、黄色の固体として８１％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）：δ＝７．５７（ｓ，１Ｈ）、７．２３（ｓ，１Ｈ）、６．５５（ｓ，１Ｈ）、４．６３（ｂｒ ｓ，２Ｈ）、３．４５（ｂｒ ｓ，１Ｈ）、３．３５（ｓ，３Ｈ）、２．８５（ｂｒ ｓ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₆Ｈ₁₂Ｃｌ₂Ｎ₄Ｏ₂［Ｍ＋Ｈ］⁺に対する計算値：３６３．０；実測値：３６３．１．

1- (2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethane-1-one ( 55). 4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (20 mg, 0.062 mmol) in DCM (1 mL) To the flask containing, dry K ₂ CO ₃ (30 mg, 0.22 mmol) and acetyl chloride (0.006 mL, 0.074 mmol) were added at 0 ° C. The reaction was stirred at room temperature for 8 hours. The reaction was then quenched by the addition of 1N aqueous NaOH solution (1 mL) and stirred at room temperature for 1 hour. The reaction was taken up in DCM (10 mL) and washed with saturated aqueous NaHCO ₃ solution (10 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a yellow solid in 81% yield.
^{1 1} H NMR (400 MHz, CDCl3): δ = 7.57 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H), 4.63 (br s, 2H), 3. 45 (br s, 1H), 3.35 (s, 3H), 2.85 (br s, 1H). HPLC / MS: m / z C ₁₆ H ₁₂ Cl ₂ N ₄ O ₂ [M + H] ⁺ Calculated value: 363.0; Measured value: 363.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−７−カルバルデヒド（５６）。乾燥ＴＨＦ（２ｍＬ）を含むフラスコに、乾燥ＤＭＦ（０．１ｍＬ）およびＰＯＣｌ₃（０．０１５ｍＬ、０．１６ｍｍｏｌ）を０℃で加えた。反応物を、アルゴン下で、０℃で３０分間撹拌し、その直後に、ＴＨＦ（１ｍＬ）中の４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０ｍｇ、０．０６２ｍｍｏｌ）を滴下して加えた。反応物を、室温に温めながら８時間撹拌させた。次に、反応物に、１ＮのＮａＯＨ水溶液（２ｍＬ）を加え、１時間にわたって８０℃に加熱した。反応物を室温に冷まし、ＥｔＯＡｃ（２０ｍＬ）に取り込み、飽和ＮａＨＣＯ₃水溶液（２０ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、白色の固体として５８％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）：δ＝１０．０５（ｓ，１Ｈ）、７．９６（ｓ，１Ｈ）、７．２４（ｓ，１Ｈ）、４．６３（ｂｒ ｓ，２Ｈ）、３．３１（ｂｒ ｓ，１Ｈ）、２．８５（ｂｒ ｓ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₅Ｈ₁₀Ｃｌ₂Ｎ₄Ｏ₂［Ｍ＋Ｈ］⁺に対する計算値：３４９．０；実測値：３４９．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo [3,2-d] pyrimidine-7-carbaldehyde (56). Dry DMF (0.1 mL) and POCl ₃ (0.015 mL, 0.16 mmol) were added to a flask containing dry THF (2 mL) at 0 ° C. The reaction is stirred under argon at 0 ° C. for 30 minutes, immediately followed by 4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -5H-pyrrolo in THF (1 mL). [3,2-d] Pyrimidine-2-amine (20 mg, 0.062 mmol) was added dropwise. The reaction was stirred for 8 hours while warming to room temperature. Next, a 1N aqueous NaOH solution (2 mL) was added to the reaction product, and the mixture was heated to 80 ° C. for 1 hour. The reaction was cooled to room temperature, incorporated into EtOAc (20 mL) and washed with saturated aqueous NaHCO ₃ solution (20 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a white solid in 58% yield.
^{1 1} H NMR (400 MHz, CDCl3): δ = 10.05 (s, 1H), 7.96 (s, 1H), 7.24 (s, 1H), 4.63 (br s, 2H), 3. 31 (br s, 1H), 2.85 (br s, 1H). HPLC / MS: m / z C ₁₅ H ₁₀ Cl ₂ N ₄ O ₂ [M + H] ⁺ Calculated value: 349.0; Measured value: 349.1.

７−ブロモ−４−（２，４−ジクロロ−５−メトキシフェニル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（５７）。ＡｃＯＨ：ｔＢｕＯＨ（５０：５０、０．５ｍＬ：０．５ｍＬ）中の４−（２，４−ジクロロ−５−メトキシフェニル）−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−２−アミン（２０ｍｇ、０．０６５ｍｍｏｌ）を含むフラスコに、ＬｉＢｒ（１８ｍｇ、０．２２ｍｍｏｌ）、およびＢｒ₂（０．０１１ｍＬ、０．２２ｍｍｏｌ）を０℃で加えた。反応物を室温で８時間撹拌させた。その後、反応物を、ＥｔＯＡｃ（２０ｍＬ）に取り込み、飽和ＮａＨＣＯ₃水溶液（３×２０ｍＬ）、およびＮａ₂Ｓ₂Ｏ₃（１０重量％水溶液、２０ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、黄色の固体として５６％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．７５（ｓ，１Ｈ）、７．７２（ｓ，１Ｈ）、７．２６（ｓ，１Ｈ）、６．２４（ｓ，２Ｈ）、３．８６（ｓ，３Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₃Ｈ₉ＢｒＣｌ₂Ｎ₄Ｏ［Ｍ＋Ｈ］⁺に対する計算値：３８６．９；実測値：３８７．０．

7-Bromo-4- (2,4-dichloro-5-methoxyphenyl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (57). AcOH: 4- (2,4-dichloro-5-methoxyphenyl) -5H-pyrrolo [3,2-d] pyrimidin-2-amine (20 mg) in tBuOH (50:50, 0.5 mL: 0.5 mL) , 0.065 mmol) was added LiBr (18 mg, 0.22 mmol) and Br ₂ (0.011 mL, 0.22 mmol) at 0 ° C. The reaction was stirred at room temperature for 8 hours. The reaction was then taken up in EtOAc (20 mL) and washed with saturated aqueous NaHCO ₃ solution (3 x 20 mL) and Na ₂ S ₂ O ₃ (10 wt% aqueous solution, 20 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a yellow solid in 56% yield.
^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.75 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H), 6.24 (s, 2H), 3 .86 (s, 3H). HPLC / MS: m / z C ₁₃ H ₉ BrCl ₂ N ₄ O [M + H] ⁺ Calculated value: 386.9; Measured value: 387.0.

工程１：前駆体２，５−ジオキソピロリジン−１−イル２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキシレートの合成。
脱気したＤＭＦ：Ｈ₂Ｏ（５０：５０；２ｍＬ：２ｍＬ）を含むフラスコに、エチル２−アミノ−４−クロロチエノ［２，３−ｄ］ピリミジン−６−カルボキシレート（１００ｍｇ、０．３９ｍｍｏｌ）、（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）ボロン酸（９１ｍｇ、０．３９ｍｍｏｌ）、ＮａＨＣＯ₃（８２ｍｇ、０．９８ｍｍｏｌ）、およびＰｄ（ＰＰｈ₃）₄（２２ｍｇ、０．０２ｍｍｏｌ）を室温で加えた。続いて、反応物を、アルゴン下で、８０℃で８時間加熱した。反応物を冷まし、酢酸エチル（２０ｍＬ）に取り込み、塩水（３×２０ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物エチル２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキシレートが、黄色の固体として３８％の収率で得られた。 General procedure for the synthesis of 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidin-6-carboxamide:

Step 1: Precursor 2,5-dioxopyrrolidine-1-yl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine- Synthesis of 6-carboxylate.
In a flask containing degassed DMF: H ₂ O (50:50; 2 mL: 2 mL), ethyl 2-amino-4-chlorothieno [2,3-d] pyrimidin-6-carboxylate (100 mg, 0.39 mmol) , (5,7-Dichloro-2,3-dihydrobenzofuran-4-yl) boronic acid (91 mg, 0.39 mmol), NaHCO ₃ (82 mg, 0.98 mmol), and Pd (PPh ₃ ) ₄ (22 mg, 0). .02 mmol) was added at room temperature. Subsequently, the reaction was heated under argon at 80 ° C. for 8 hours. The reaction was cooled, incorporated into ethyl acetate (20 mL) and washed with brine (3 x 20 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product ethyl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidin-6-carboxylate is 38% as a yellow solid. Obtained in yield.

Ethyl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxylate (60 mg, 0.15 mmol) in THF ( It was dissolved in 1 mL), and 1N aqueous NaOH solution (1 mL) was added to the flask. The reaction was stirred at room temperature for 8 hours. The solution was then cooled to 0 ° C. and acidified by the addition of 1N aqueous HCl (2 mL) to form a white precipitate, which was filtered and dried to give 2-amino-4- ( 5,7-Dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidin-6-carboxylic acid was obtained in quantitative yield without further purification. Filter (filtrand) (57 mg, 0.15 mmol) was dissolved in dry DMF (1 mL), cooled to 0 ° C., and N-hydroxysuccinimide (23 mg, 0.2 mmol) and 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide HCl (38 mg, 0.2 mmol) was added. The reaction was stirred for 8 hours while warming to room temperature. The solution was taken up in DCM (20 mL) and washed with saturated aqueous NH ₄ Cl solution (3 x 20 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). Product 2,5-dioxopyrrolidine-1-yl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxy The rate was obtained as a white solid in 88% yield.

２，５−ジオキソピロリジン−１−イル２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキシレート（１０ｍｇ、０．０２ｍｍｏｌ）を含むフラスコに、乾燥ＤＭＦ（０．５ｍＬ）を加えた後、アミン（３当量、０．０６ｍｍｏｌ）、（例えばアンモニア、第一級アミン、または第二級アミン）を加えた。反応物を室温で１２時間撹拌させ、その直後、それをＤＣＭ（５ｍＬ）に取り込み、飽和ＮＨ₄Ｃｌ水溶液（３×５ｍＬ）で洗浄した。有機層をＮａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。得られたアミドは、良好ないし優良な収率で得られた。 Step 2: General procedure for the formation of amides:

2,5-Dioxopyrrolidine-1-yl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxylate (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) Dry DMF (0.5 mL) is added to a flask containing 10 mg (0.02 mmol), followed by amine (3 equivalents, 0.06 mmol) (eg ammonia, primary amine, or secondary amine). It was. The reaction was stirred at room temperature for 12 hours, immediately followed by incorporation into DCM (5 mL) and washed with saturated aqueous NH ₄ Cl solution (3 x 5 mL). The organic layer was dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The obtained amide was obtained in good or good yield.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（２−（ピロリジン−１−イル）エチル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（５８）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．７９（ｓ，１Ｈ）、７．６１（ｓ，１Ｈ）、７．５８（ｓ，１Ｈ）、７．２８（ｓ，２Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．４４−３．１１（ｍ，６Ｈ）、２．９０−２．７５（ｍ，４Ｈ）、１．７７−１．７３（ｍ，４Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₂₁Ｈ₂₁Ｃｌ₂Ｎ₅Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４７８．１；実測値：４７８．１

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (2- (pyrrolidin-1-yl) ethyl) thieno [2,3-d] pyrimidine-6 -Carboxamide (58). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.79 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.28 (s, 2H), 4 .67 (t, J = 8.8Hz, 2H), 3.44-3.11 (m, 6H), 2.90-2.75 (m, 4H), 1.77-1.73 (m, 4H). HPLC / MS: m / z C ₂₁ H ₂₁ Cl ₂ N ₅ O ₂ S [M + H] ⁺ Calculated value: 478.1; Measured value: 478.1

２−アミノ−Ｎ−（２−シアノエチル）−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（５９）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．９４（ｔ，Ｊ＝５．６Ｈｚ、１Ｈ）、７．６３（ｓ，１Ｈ）、７．６０（ｓ，１Ｈ）、７．３４（ｓ，２Ｈ）、４．６９（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．４６−３．４１（ｍ，２Ｈ）、３．２３−３．１５（ｍ，１Ｈ）、３．０３−２．９７（ｍ，１Ｈ）、２．７６（ｔ，Ｊ＝６．４Ｈｚ、２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₈Ｈ₁₃Ｃｌ₂Ｎ₅Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３４．０；実測値：４３４．１．

2-Amino-N- (2-cyanoethyl) -4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxamide (59). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.94 (t, J = 5.6 Hz, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.34 ( s, 2H), 4.69 (t, J = 8.8Hz, 2H), 3.46-3.41 (m, 2H), 3.23-3.15 (m, 1H), 3.03- 2.97 (m, 1H), 2.76 (t, J = 6.4Hz, 2H). HPLC / MS: m / z C ₁₈ H ₁₃ Cl ₂ N ₅ O ₂ S [M + H] ⁺ Calculated value: 434.0; Measured value: 434.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（２−ヒドロキシエチル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６０）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．５７（ｔ，Ｊ＝５．６Ｈｚ、１Ｈ）、７．５９（ｓ，２Ｈ）、７．２６（ｓ，２Ｈ）、４．７３（ｔ，Ｊ＝５．６Ｈｚ、１Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．４６−３．４１（ｍ，２Ｈ）、３．２６−３．１２（ｍ，３Ｈ）、３．０３−２．９４（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₄Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４２５．０；実測値：４２５．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (2-hydroxyethyl) thieno [2,3-d] pyrimidin-6-carboxamide (60). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.57 (t, J = 5.6 Hz, 1H), 7.59 (s, 2H), 7.26 (s, 2H), 4.73 ( t, J = 5.6Hz, 1H), 4.67 (t, J = 8.8Hz, 2H), 3.46-3.41 (m, 2H), 3.26-3.12 (m, 3H) ), 3.03-2.94 (m, 1H). HPLC / MS: m / z C ₁₇ H ₁₄ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 425.0; Measured value: 425.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（２，２，２−トリフルオロエチル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６１）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝９．１８（ｔ，Ｊ＝６．０Ｈｚ、１Ｈ）、７．７２（ｓ，１Ｈ）、７．６３（ｓ，１Ｈ）、７．３８（ｓ，２Ｈ）、４．６９（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、４．１２−４．０３（ｍ，２Ｈ）、３．２６−３．１８（ｍ，１Ｈ）、３．０３−２．９４（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₁Ｃｌ₂Ｆ₃Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４６３．０；実測値：４６３．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine-6- Carboxamide (61). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 9.18 (t, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.38 ( s, 2H), 4.69 (t, J = 8.8Hz, 2H), 4.12-4.03 (m, 2H), 3.26-3.18 (m, 1H), 3.03- 2.94 (m, 1H). HPLC / MS: m / z C ₁₇ H ₁₁ Cl ₂ F ₃ N ₄ O ₂ S [M + H] ⁺ Calculated value: 463.0; Measured value: 463.1.

２−アミノ−Ｎ−シクロプロピル−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６２）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．５４（ｓ，１Ｈ）、７．６１（ｓ，１Ｈ）、７．５３（ｓ，１Ｈ）、７．２９（ｓ，２Ｈ）、４．６８（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２６−３．１８（ｍ，１Ｈ）、３．０３−２．９４（ｍ，１Ｈ）、２．８１−２．７１（ｍ，１Ｈ）、０．７５−０．６１（ｍ，２Ｈ）、０．５５−０．４０（ｍ，２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₈Ｈ₁₄Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４２１．０；実測値：４２１．１．

2-Amino-N-cyclopropyl-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxamide (62). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.54 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.29 (s, 2H), 4 .68 (t, J = 8.8Hz, 2H), 3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H), 2.81-2.71 (m, 1H), 0.75-0.61 (m, 2H), 0.55-0.40 (m, 2H). HPLC / MS: m / z C ₁₈ H ₁₄ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 421.0; Measured value: 421.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６３）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．６２−８．５９（ｍ，１Ｈ）、７．６１（ｓ，２Ｈ）、７．２７（ｓ，２Ｈ）、４．６４（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２４（ｓ，３Ｈ）、３．２３−３．１８（ｍ，１Ｈ）、３．０３−２．９１（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₆Ｈ₁₂Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：３９５．０；実測値：３９５．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methylthieno [2,3-d] pyrimidine-6-carboxamide (63). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.62-8.59 (m, 1H), 7.61 (s, 2H), 7.27 (s, 2H), 4.64 (t, J = 8.8Hz, 2H), 3.24 (s, 3H), 3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H). HPLC / MS: m / z C ₁₆ H ₁₂ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 395.0; Measured value: 395.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（２−メトキシエチル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６４）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．５１−８．４１（ｍ，１Ｈ）、７．５９（ｓ，１Ｈ）、７．５０（ｓ，１Ｈ）、７．２６（ｓ，２Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２３−３．１０（ｍ，４Ｈ）、３．０３−２．９１（ｍ，２Ｈ）、２．７２−２．６７（ｍ，３Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₈Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３９．０；実測値：４３９．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (2-methoxyethyl) thieno [2,3-d] pyrimidin-6-carboxamide (64). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.51-8.41 (m, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.26 (s, 2H), 4.67 (t, J = 8.8Hz, 2H), 3.23-3.10 (m, 4H), 3.03-2.91 (m, 2H), 2.72-2. 67 (m, 3H). HPLC / MS: m / z C ₁₈ H ₁₆ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 439.0; Measured value: 439.1.

２−アミノ−Ｎ−シクロブチル−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６５）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．６８（ｄ，Ｊ＝６．８Ｈｚ、１Ｈ）、７．６１（ｓ，１Ｈ）、７．５６（ｓ，１Ｈ）、７．２６（ｓ，２Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、４．３３−４．２６（ｍ，１Ｈ）、３．２３−３．１８（ｍ，１Ｈ）、３．０３−２．９１（ｍ，１Ｈ）、２．１６−１．９２（ｍ，２Ｈ）、１．７０−１．６０（ｍ，１Ｈ）、１．３３−１．２０（ｍ，２Ｈ）、０．９０−０．７８（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３５．０；実測値：４３５．１．

2-Amino-N-cyclobutyl-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxamide (65). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.26 ( s, 2H), 4.67 (t, J = 8.8Hz, 2H), 4.33-4.26 (m, 1H), 3.23-3.18 (m, 1H), 3.03- 2.91 (m, 1H), 2.16-1.92 (m, 2H), 1.70-1.60 (m, 1H), 1.33-1.20 (m, 2H), 0. 90-0.78 (m, 1H). HPLC / MS: m / z C ₁₉ H ₁₆ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 435.0; Measured value: 435.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ，Ｎ−ジメチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６６）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５４（ｓ，１Ｈ）、７．２３（ｓ，２Ｈ）、７．１５（ｓ，１Ｈ）、４．６６（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．３１（ｓ，３Ｈ）、３．２３−２．９０（ｍ，５Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₄Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４０９．０；実測値：４０９．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N, N-dimethylthieno [2,3-d] pyrimidine-6-carboxamide (66). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.15 (s, 1H), 4.66 (t, J = 8. 8Hz, 2H), 3.31 (s, 3H), 3.23-2.90 (m, 5H). HPLC / MS: m / z C ₁₇ H ₁₄ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 409.0; Measured value: 409.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（オキセタン−３−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（６７）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝９．１７（ｄ，Ｊ＝６．８Ｈｚ、１Ｈ）、７．６４（ｓ，１Ｈ）、７．６２（ｓ，１Ｈ）、７．３１（ｓ，２Ｈ）、４．９７−４．９０（ｍ，１Ｈ）、４．７５−４．６５（ｍ，４Ｈ）、４．５５−４．４５（ｍ，２Ｈ）、３．２０−３．１１（ｍ，１Ｈ）、３．０２−２．９２（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₈Ｈ₁₄Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３７．０；実測値：４３７．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (oxetane-3-yl) thieno [2,3-d] pyrimidine-6-carboxamide (67) .. ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 9.17 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.31 ( s, 2H), 4.97-4.90 (m, 1H), 4.75-4.65 (m, 4H), 4.55-4.45 (m, 2H), 3.20-3. 11 (m, 1H), 3.02-2.92 (m, 1H). HPLC / MS: m / z C ₁₈ H ₁₄ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 437.0; Measured value: 437.1.

（２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−イル）（モルホリノ）メタノン（６８）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５４（ｓ，１Ｈ）、７．２３（ｓ，２Ｈ）、７．１２（ｓ，１Ｈ）、４．６６（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．５９（ｂｒ ｓ，８Ｈ）、３．２６−３．２１（ｍ，１Ｈ）、３．０２−２．９２（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４５１．０；実測値：４５１．１．

(2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-yl) (morpholino) methanone (68). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.12 (s, 1H), 4.66 (t, J = 8. 8Hz, 2H), 3.59 (br s, 8H), 3.26-3.21 (m, 1H), 3.02-2.92 (m, 1H). HPLC / MS: m / z C ₁₉ H ₁₆ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 451.0; Measured value: 451.1.

（２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−イル）（ピロリジン−１−イル）メタノン（６９）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５４（ｓ，１Ｈ）、７．２３（ｓ，２Ｈ）、７．２１（ｓ，１Ｈ）、４．６６（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．６８−３．６４（ｍ，２Ｈ）、３．４４（ｂｒ ｓ，２Ｈ）、３．２６−３．１６（ｍ，１Ｈ）、３．０２−２．９２（ｍ，１Ｈ）、１．９１−１．７６（ｍ，４Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３５．０；実測値：４３５．１．

(2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidin-6-yl) (pyrrolidine-1-yl) metanone (69) .. ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.23 (s, 2H), 7.21 (s, 1H), 4.66 (t, J = 8. 8Hz, 2H), 3.68-3.64 (m, 2H), 3.44 (br s, 2H), 3.26-3.16 (m, 1H), 3.02-2.92 (m) , 1H), 1.91-1.76 (m, 4H). HPLC / MS: m / z C ₁₉ H ₁₆ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 435.0; Measured value: 435.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メチル−Ｎ−（２，２，２−トリフルオロエチル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７０）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５４（ｓ，１Ｈ）、７．３３（ｓ，３Ｈ）、４．６６（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、４．４１−４．２８（ｍ，２Ｈ）、３．２７（ｓ，３Ｈ）、３．２６−３．１６（ｍ，１Ｈ）、３．０２−２．９２（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₈Ｈ₁₃Ｃｌ₂Ｆ₃Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４７７．０；実測値：４７７．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methyl-N- (2,2,2-trifluoroethyl) thieno [2,3-d] Pyrimidine-6-carboxamide (70). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.33 (s, 3H), 4.66 (t, J = 8.8 Hz, 2H), 4.41- 4.28 (m, 2H), 3.27 (s, 3H), 3.26-3.16 (m, 1H), 3.02-2.92 (m, 1H). HPLC / MS: m / z C ₁₈ H ₁₃ Cl ₂ F ₃ N ₄ O ₂ S [M + H] ⁺ Calculated value: 477.0; Measured value: 477.1.

２−アミノ−Ｎ−（２−シアノエチル）−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７１）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５４（ｓ，１Ｈ）、７．２８（ｓ，２Ｈ）、７．２０（ｓ，１Ｈ）、４．６６（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．６９（ｂｒ ｓ，２Ｈ）、３．２６−３．１６（ｍ，４Ｈ）、３．０２−２．９２（ｍ，１Ｈ）、２．８２−２．７０（ｍ，２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₅Ｃｌ₂Ｎ₅Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４４８．０；実測値：４４８．１．

2-Amino-N- (2-cyanoethyl) -4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methylthieno [2,3-d] pyrimidine-6-carboxamide (71) ). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.28 (s, 2H), 7.20 (s, 1H), 4.66 (t, J = 8. 8Hz, 2H), 3.69 (br s, 2H), 3.26-3.16 (m, 4H), 3.02-2.92 (m, 1H), 2.82-2.70 (m) , 2H). HPLC / MS: m / z C ₁₉ H ₁₅ Cl ₂ N ₅ O ₂ S [M + H] ⁺ Calculated value: 448.0; Measured value: 448.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メチル−Ｎ−（オキセタン−３−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７２）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５５（ｓ，１Ｈ）、７．２６（ｓ，２Ｈ）、７．１６（ｓ，１Ｈ）、５．２１−５．１６（ｍ，１Ｈ）、４．６９−４．６０（ｍ，６Ｈ）、３．２６−３．１４（ｍ，４Ｈ）、３．０２−２．９２（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４５１．０；実測値：４５１．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methyl-N- (oxetane-3-yl) thieno [2,3-d] pyrimidine-6- Carboxamide (72). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 1H), 7.26 (s, 2H), 7.16 (s, 1H), 5.21-5.16 (m, 1H), 4.69-4.60 (m, 6H), 3.26-3.14 (m, 4H), 3.02-2.92 (m, 1H). HPLC / MS: m / z C ₁₉ H ₁₆ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 451.0; Measured value: 451.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−（２−ヒドロキシ−２−メチルプロピル）チエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７３）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝８．４４（ｓ，１Ｈ）、７．６９（ｓ，１Ｈ）、７．５９（ｓ，１Ｈ）、７．２３（ｓ，２Ｈ）、４．６７（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、４．４５（ｓ，１Ｈ）、３．２１−３．１２（ｍ，３Ｈ）、３．０２−２．９２（ｍ，１Ｈ）、１．０４（ｓ，６Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₈Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４５３．０；実測値：４５３．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N- (2-hydroxy-2-methylpropyl) thieno [2,3-d] pyrimidine-6-carboxamide (73). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.23 (s, 2H), 4 .67 (t, J = 8.8Hz, 2H), 4.45 (s, 1H), 3.21-3.12 (m, 3H), 3.02-2.92 (m, 1H), 1 .04 (s, 6H). HPLC / MS: m / z C ₁₉ H ₁₈ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 453.0; Measured value: 453.1.

２−アミノ−Ｎ−シクロプロピル−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７４）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５５（ｓ，１Ｈ）、７．３６（ｓ，１Ｈ）、７．２８（ｓ，２Ｈ）、４．７０−４．６２（ｍ，２Ｈ）、３．１３−３．０６（ｍ，１Ｈ）、３．００−２．９１（ｍ，４Ｈ）、０．８０−０．７２（ｍ，２Ｈ）、０．６８−０．６３（ｍ，２Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₉Ｈ₁₆Ｃｌ₂Ｎ₄Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４３５．０；実測値：４３５．１．

2-Amino-N-cyclopropyl-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methylthieno [2,3-d] pyrimidine-6-carboxamide (74). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 1H), 7.36 (s, 1H), 7.28 (s, 2H), 4.70-4.62 (m, 2H), 3.13-3.06 (m, 1H), 3.00-2.91 (m, 4H), 0.80-0.72 (m, 2H), 0.68-0.63 ( m, 2H). HPLC / MS: m / z C ₁₉ H ₁₆ Cl ₂ N ₄ O ₂ S [M + H] ⁺ Calculated value: 435.0; Measured value: 435.1.

２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メトキシ−Ｎ−メチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（７５）。¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５７（ｓ，１Ｈ）、７．４７（ｓ，１Ｈ）、７．３７（ｓ，２Ｈ）、４．７０−４．６２（ｍ，２Ｈ）、３．７４（ｓ，３Ｈ）、３．２７−３．１９（ｍ，４Ｈ）、３．００−２．９１（ｍ，１Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₄Ｃｌ₂Ｎ₄Ｏ₃Ｓ［Ｍ＋Ｈ］⁺に対する計算値：４２５．０；実測値：４２５．１．

2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methoxy-N-methylthieno [2,3-d] pyrimidine-6-carboxamide (75). ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.57 (s, 1H), 7.47 (s, 1H), 7.37 (s, 2H), 4.70-4.62 (m, 2H), 3.74 (s, 3H), 3.27-3.19 (m, 4H), 3.00-2.91 (m, 1H). HPLC / MS: m / z C ₁₇ H ₁₄ Cl ₂ N ₄ O ₃ S [M + H] ⁺ Calculated value: 425.0; Measured value: 425.1.

１−（２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−イル）プロパン−１−オン（７６）。乾燥ＴＨＦ（１ｍＬ）中の２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）−Ｎ−メトキシ−Ｎ−メチルチエノ［２，３−ｄ］ピリミジン−６−カルボキサミド（２０ｍｇ、０．０４８ｍｍｏｌ）を含むフラスコに、０℃でＥｔＭｇＢｒ（ＴＨＦ中２．０Ｍ；０．０２９ｍＬ、０．０５７ｍｍｏｌ）を加えた。反応物を８時間撹拌し、その直後に、それを飽和ＮＨ₄Ｃｌ水溶液（１ｍＬ）の添加によってクエンチした。水層をＥｔＯＡｃ（３×２ｍＬ）で抽出し、Ｎａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、白色の固体として９１％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ₃）：δ＝７．４１（ｓ，１Ｈ）、７．３４（ｓ，１Ｈ）、５．８４（ｂｒ ｓ，２Ｈ）、４．７４−４．６４（ｍ，２Ｈ）、３．８７−３．７６（ｍ，１Ｈ）、３．３０−３．１０（ｍ，３Ｈ）、１．５０−１．４１（ｍ，３Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₃Ｃｌ₂Ｎ₃Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：３９４．０；実測値：３９４．１．

1- (2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-yl) propan-1-one (76). 2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) -N-methoxy-N-methylthieno [2,3-d] pyrimidin-6- in dry THF (1 mL) EtMgBr (2.0 M in THF; 0.029 mL, 0.057 mmol) was added to a flask containing carboxamide (20 mg, 0.048 mmol) at 0 ° C. The reaction was stirred for 8 hours, immediately followed by quenching by the addition of saturated aqueous NH ₄ Cl solution (1 mL). The aqueous layer was extracted with EtOAc (3 x 2 mL), dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a white solid in 91% yield.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ = 7.41 (s, 1H), 7.34 (s, 1H), 5.84 (br s, 2H), 4.74-4.64 (m, 2H), 3.87-3.76 (m, 1H), 3.30-3.10 (m, 3H), 1.50-1.41 (m, 3H). HPLC / MS: m / z C ₁₇ H ₁₃ Cl ₂ N ₃ O ₂ S [M + H] ⁺ Calculated value: 394.0; Measured value: 394.1.

２−（２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−イル）プロパン−２−オール（７７）。乾燥ＴＨＦ（１ｍＬ）中のエチル２−アミノ−４−（５，７−ジクロロ−２，３−ジヒドロベンゾフラン−４−イル）チエノ［２，３−ｄ］ピリミジン−６−カルボキシレート（２０ｍｇ、０．０４８ｍｍｏｌ）を含むフラスコに、０℃でＭｅＭｇＢｒ（ＴＨＦ中２．０Ｍ；０．０７２ｍＬ、０．１４４ｍｍｏｌ）を加えた。反応物を８時間撹拌し、その直後に、それを飽和ＮＨ₄Ｃｌ水溶液（１ｍＬ）の添加によってクエンチした。水層をＥｔＯＡｃ（３×２ｍＬ）で抽出し、Ｎａ₂ＳＯ₄上で乾燥させ、ろ過し、揮発性物質を蒸発させた。残渣を、ＤＣＭ：ＭｅＯＨ（１００：０〜９０：１０）の勾配を用いたシリカゲルクロマトグラフィーによって精製した。生成物が、白色の固体として７８％の収率で得られた。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）：δ＝７．５３（ｓ，１Ｈ）、６．８５（ｓ，２Ｈ）、６．５４（ｓ，１Ｈ）、５．９５（ｓ，１Ｈ）、４．６４（ｔ，Ｊ＝８．８Ｈｚ、２Ｈ）、３．２０−３．１２（ｍ，１Ｈ）、３．００−２．９０（ｍ，１Ｈ）、１．４６（ｓ，３Ｈ）、１．４４（ｓ，３Ｈ）．ＨＰＬＣ／ＭＳ：ｍ／ｚ Ｃ₁₇Ｈ₁₅Ｃｌ₂Ｎ₃Ｏ₂Ｓ［Ｍ＋Ｈ］⁺に対する計算値：３９６．０；実測値：３９６．１．

2- (2-Amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidin-6-yl) propan-2-ol (77). Ethyl 2-amino-4- (5,7-dichloro-2,3-dihydrobenzofuran-4-yl) thieno [2,3-d] pyrimidine-6-carboxylate (20 mg, 0) in dry THF (1 mL) MeMgBr (2.0 M in THF; 0.072 mL, 0.144 mmol) was added to a flask containing (0.048 mmol) at 0 ° C. The reaction was stirred for 8 hours, immediately followed by quenching by the addition of saturated aqueous NH ₄ Cl solution (1 mL). The aqueous layer was extracted with EtOAc (3 x 2 mL), dried over Na ₂ SO ₄ and filtered to evaporate the volatiles. The residue was purified by silica gel chromatography using a gradient of DCM: MeOH (100: 0-90: 10). The product was obtained as a white solid in 78% yield.
^{1 1} H NMR (400 MHz, DMSO-d6): δ = 7.53 (s, 1H), 6.85 (s, 2H), 6.54 (s, 1H), 5.95 (s, 1H), 4 .64 (t, J = 8.8Hz, 2H), 3.20-3.12 (m, 1H), 3.00-2.90 (m, 1H), 1.46 (s, 3H), 1 .44 (s, 3H). HPLC / MS: m / z C ₁₇ H ₁₅ Cl ₂ N ₃ O ₂ S [M + H] ⁺ Calculated value: 396.0; Measured value: 396.1.

Example 2. In vitro assay of the compounds of the invention Hsp90 biochemical assay (fluorescent polarized light)
The Hsp90 inhibitory activity of the compounds of the invention was evaluated using a fluorescent polarization (FP) assay using FITC-labeled geldanamycin and a truncated α-Hsp90 protein. The binding activity was measured with a BMG CLARIOstar® reader (BMG Labtech, Ortenberg, Germany). This assay is a homogeneous system (homogeneus), performed in 384-well plates, and always using known standards. Assays were validated with known Hsp90 inhibitors consistent with reported IC _50s (Luo et al., Supra), such as PU-H71 (IC ₅₀ = 60 nM). The results of this assay for compounds 20, 36, 37, and 39 and known Hsp90 inhibitors are shown in FIG.

Hsp90 Biochemical Assay (AlphaLISA)
The Hsp90 inhibitory activity of the compounds of the present invention was developed in the AlphaLISA format (PerkinElmer, Inc., Waltham, MA; the format of this assay is, for example, ELISA to AlphaLISA Conversion Guide (PerkinElmer, Inc.) published in August 2012. ) Was evaluated using a robust and reproducible assay based on). The assay uses beads coated with biotinylated geldanamycin, His-tagged Hsp90, and Ni ^{+ 2} . The assay is homogeneous and miniaturized to a 384-well plate. The binding activity was measured in an Envision reader. Assays were validated with known Hsp90 inhibitors, including PU-H71 (IC ₅₀ = 60 nM), consistent with the reported IC ₅₀ (Luo et al., Supra). This assay is the main assay for evaluating the compounds of the invention. In this assay, compound 20 showed Hsp90 inhibitory activity (0.74 ± 0.1 μM IC ₅₀ ; see FIG. 5A).

Functional Assays Based on Hsp90 Cells Cells were treated with the compounds of the invention for 24 hours and then dissolved in buffer containing NP-40, orthovanadet, and protease inhibitors. Western blots were performed with antibodies specific for Hsp70, Hsp90, or actin (as a control). Using the SHSY5Y-hTau441V337M / R406W cell line (Loeffler et al., J. Mol. Neurosci., 47: 192-203, 2012), for example, Liu et al. , Biochemistry, 49: 4921-4929, 2010, was used to assay taurine oxidation. This cell line is a stable transfected cell line that has been shown to have hyperphosphorylated tau by overexpressing hTAU441, the longest human tau isoform with two mutations: V337M and R406W. Represent. The functional assays described herein provide an in vitro model of tauopathy and can be used to assess the effect of Hsp90 inhibitors on phosphorylated tau protein (p-tau). In these assays, compound 20 increased expression of Hsp70 (see FIG. 5B), significantly reduced levels of pTau231 at 0.1 and 0.5 μM (see FIG. 6B), and 0.05, 0. A significant reduction in the level of pTau396 at 1 and 0.5 μM (see FIG. 6C) was shown.

Cytotoxicity Assay SH-SY5Y-hTAU441 Cell viability was measured using the MTT assay. As shown in FIG. 6A, compound 20 did not affect the cell viability of SH-SY5Y-hTAU441 cells. SH-SY5Y cell viability can also be measured after 24 and 48 hours using the CellTiter-Glo® assay to measure ATP levels. In addition, cytotoxicity can be assessed using Celigo® with live cell microscopy and GE InCell Analyzer 2000 to measure multiple results including apoptosis markers, membrane permeability, and mitochondrial activity.

Mouse Liver Microsome Stability The metabolic stability of the compounds of the invention was evaluated by monitoring the degradation of mouse liver microsomes. Compound 20 showed good microsomal stability (T _1/2 = 26 minutes).

Solubility The solubility of the compound was measured in a pH 7.4 buffer. Water solubility of about 0.5 μM or more (eg, about 1 μM or more, about 2 μM or more, about 5 μM or more, about 10 μM or more, about 20 μM or more, or about 30 μM or more) is for medical use, for example, for neurodegenerative diseases. It may indicate a compound with acceptable solubility for treatment. At a pH of 7.4, compound 20 exhibits 30 μM water solubility.

Cell-permeable compounds can be evaluated in the MDR1-MDCK permeability assay or Caco-2 permeability assay to measure their permeability. Permeability from apical (A) (A) to basal (B) greater than 3 × 10 ^-6 cm / sec and less than 3 B → A / A → B asymmetry to the compound is brain permeability. A compound that is considered an acceptable predictor and has such properties is unlikely to be a P-glycoprotein (P-gp) substrate. Compound 20 showed excellent permeability in the MDR1-MDCK assay (AB = 28 × 10 ^-6 cm / sec) with low asymmetry (B → A / A → B asymmetry = 0.9). ..

The results of the above assay for the particular compounds of the invention are summarized in Table 3.

Example 3. Pharmacokinetic Properties of Compounds of the Invention Preclinical studies included 85 mice divided into 6 groups; a summary of treatment groups is shown in Table 4.

Plasma and brain samples were taken before administration, 15 and 30 minutes, 1, 2, and 8 hours before and after administration. The pre-dose group had 5 animals, while the post-dose group had 3 animals.

Biological analysis method Biological analysis of mouse plasma samples for compound 20 was performed by protein precipitation and LC-MS / MS using compound 22 as an internal standard. This method is based on a "generic assay", and some method developments have been done to tailor the assay to specific compounds and internal standards. The final non-GLP assay was first tested by analyzing the performance of bioanalysis using spiked mouse plasma samples. The implementation of the qualification passed the run acceptance criteria (see below). Next, biological analysis of plasma sample extract and brain sample homogenate extract was performed using calibration and quality control samples added to mouse samples. The assay will be described later.

Treatment of Assay Samples for Mouse Plasma Concentrations of Compound 20 Compound 20 and Compound 22 were extracted from the mouse plasma matrix by protein precipitation. To 20.0 μL of sample, 10.0 μL of internal standard solution (1000 ng / mL in MeOH) and 200 μL of MeOH were added. The mixture was vortexed (about 5 seconds) and centrifuged (14000 rpm, 5 minutes). Next, the supernatant was collected and evaporated to dryness. The residue was redissolved in 100 μL of redissolved solution (80: 20v: v mobile phase A: B). For analysis, 20.0 μL was injected into the LC-MS / MS system.

Chromatography All chromatography was performed using a Type 1100 liquid chromatograph (Agilent) equipped with an automatic injection device. The analytical column was Xbridge C18 3.5 μm 2.1 × 50 mm (Waters) used at 50 ° C. The mobile phase was a gradient composed of solvent A: 1 g / L ammonium acetate in Milli-Q water and solvent B: MeCN. The gradient was as shown in Table 5.

Mass Spectrometry All experiments were performed on an API 3000 triple quadrupole instrument (AB Siex) operated in positive turbo ion spray mode (“TIS +”). Equipment parameters were optimized during method development. The MS / MS transitions used were as shown in Table 6.

Description of Biological Analysis Experiments and Criteria The calibration range for compound 20 was set to cover concentrations of 0.988 to 20000 ng / mL. Two sets of calibration samples were used, one set in front of the test sample and the other behind the test sample. In addition, five levels of QC samples (two samples at each level) were included in the implementation as indicators of performance and for implementation decisions.

The calibration and QC sample criteria were applied as follows:
The absolute% RE (|% RE |) for individual calibration and nominal concentrations of QC samples should be within 20% (or 25% for LLOQ);
• A calibration level is considered valid when at least one of the calibration samples of the applicable concentration level is allowed by the |% RE | criteria above;
• A QC level is considered valid when at least one of the QC samples of the applicable concentration level is allowed by the |% RE | criteria described above.

The lowest and highest permissible calibration concentration levels were adopted as the lower limit LLOQ and the upper limit HLOQ.

Bioanalysis Results For Compound 20, the highest calibration level (STD L, 20000 ng / mL) did not pass the criteria because both calibration samples showed too high a bias (see Table 7). All other calibration levels of compound 20, STD A to STD K, were acceptable and a single sample at STD C and STD G showed too high a bias. As a result, the lowest level (STD A, 0.988 ng / mL) was adopted as the LLOQ and the second highest level (STD K, 8000 ng / mL) was adopted as the HLOQ. One of the results of the QC LLOQ sample and one of the results of the QC Med sample had too high a bias. The overall performance of the method in performing bioanalysis was acceptable for compound 20.

The calibration and QC concentration levels used are shown in Table 7.

The results of bioanalysis for plasma and brain samples are shown in Tables 8 and 9.

The following observations were made on plasma samples:
There was one slight response in the pre-dose sample (1 A_0 sample; found at 2.16 ng / mL). This response may have been due to slight contamination or interference with the assay. Although the selectivity of the LC-MS / MS method is generally high, the selectivity for compound 20 in plasma was not tested. Conclusions can only be reached with more elaborate qualification or even verification methods. With less than 3 LLOQs, this pre-dose response is considered negligible here.

The results of most measurements at time point B_0.25 and all measurements at time point C_0.5 exceed the upper limit of quantification (ULOQ, at 8000 ng / mL). For more reliable results, these samples will be diluted prior to analysis. It is noted that the highest calibrator at 20000 ng / mL was included in the practice but failed with respect to bias. The average back-calculated concentration of 20000 ng / mL is 14000 ng / mL, which shows a -30% bias at that level. The above ULOQ results were included in this example as guideline values to support the PK evaluation. However, the results from time B_0.25 and C_0.5 should be treated with caution.

Results from the first subject at time point B_0.25 (IRN 12) are the relatively high concentrations observed in the other two subjects at time point (IRN 14 and 16) after this first dose. Is unlikely to be close to the observed 2.66 ng / mL. Temporarily, the PK evaluation at this point was performed in both cases: (1) the average of the three exclusions of this BLOQ result and (2) the average of the two exclusions.

In a brain (homogenate) sample, one result seems to be different than expected:
Results from the first subject at time point B_0.25 (IRN 12) are the relatively high concentrations observed in the other two subjects at this first post-dose time point (IRN 14 and 16). Is unlikely to be less than LLOQ because it does not match. Note that this corresponds to the findings of plasma (IRN 12) from this subject. Temporarily, the PK evaluation at this point was performed in both cases: (1) the average of the three exclusions of this BLOQ result and (2) the average of the two exclusions.

Pharmacokinetic evaluation Pharmacokinetic parameters were evaluated by calculation from the average concentration at each time point (n = 5 before administration, n = 3 after administration). The pharmacokinetic results are summarized below.

The results of the mouse plasma pharmacokinetic evaluation are shown in Tables 10-12 and FIGS. 7 and 8. No corrections were made for inclusion of results exceeding ULOQ or results of animal IRN12 in group B_0.25.

Tables 11 and 12 show the plasma pharmacokinetic profile of compound 20.

The results of the mouse brain tissue brain tissue pharmacokinetic evaluation are shown in FIGS. 9 and 10 and Tables 13-15. No corrections were made for the inclusion of unusual results of animal IRN 12 in group B_0.25.

Tables 14 and 15 show the brain tissue pharmacokinetic profile of Compound 20.

Example 4. Effect of compounds of the invention on total and p-tau levels of cerebrospinal fluid (CSF) and tau in the tau transgenic mouse model (hTAU441) to evaluate the effect of compounds of the invention on p-tau accumulation. Therefore, humanized age-matched (eg, May-aged) transgenic mice (hTAU mice) to the tau gene were administered at low doses by intraperitoneal administration (N = 6 per arm) over 7 days. Alternatively, it can be treated with high doses of the compounds or vehicles of the invention. The dose of the compound of the present invention can be calculated based on the PK results. hTAU transgenic mice (C57BL / 6 background) overexpress TAU441 with a missense mutation V337M and R406W under the control of a brain-specific mouse Thy-1 promoter. This human mutant tau isoform is expressed at high levels and tau lesions and can be observed at an early age starting at 4 months. The severity of brain lesions correlates with aging and behavioral deficits, while movement disorders do not occur. Be disposed all animals killed, in order to establish the Hsp70 levels of total tau and p- tau and brain extracts in the CSF, MSD multi-array (multiarray) p- tau (ThR ²¹ 1) immunoadsorption (Meso Scale Discovery, Rockville, MD) can be used to quantify soluble and insoluble tau and p-tau brains (hippocampus and cerebral cortex). Specifically, animals are anesthetized with a ketamine / xylazine mixture (note: isoflurane is known to affect p-tau levels) and are warm before and during CSF and subsequent blood sampling. It can be kept in a horizontal position. The volume of CSF collected in hTAU441 is only 2-6 μL / mouse compared to some strains (2-15 μL / mouse). p-tau (ThR ²¹ 1) and total tau levels can be evaluated using phospho-PHF-tau pThR ²¹ 1 (MSD doublex kit, Meso Scale Discovery, Rockville, MD).

Administration of the compounds of the invention can result in lower p-tau levels in mice treated with the compounds of the invention compared to p-tau levels in mice treated with the vehicle.

Example 5. Effect of Compounds of the Invention on Memory and Learning in hTAU441 Transgenic Mouse Models The 5-month-old transgenic hTAU mice described in Example 3 are low dose or high daily (N = 15 per arm) for 12 weeks. A dose of a compound or vehicle of the group of the invention can be administered intraperitoneally. The corresponding untreated group of mice is analyzed as a baseline. Behavioral tests, such as the Probe Trial, the Nose Poke Curiosity and Activity Test, and the Morris Water Maze task, can be performed. After completion of the test, CSF may be collected and brain tissue can be collected from these animals. Total tau and p-tau levels can be evaluated in CSF and brain. In addition, immunohistochemical measurements of tau lesions can be performed. Tau deposition can be measured using the monoclonal antibodies AT180 (Thermo Scientific Pierce Antibodies, Rockford, IL) and HT7 (Thermo Scientific Pierce Antibodies, Rockford, IL). Sodium selenite, a PP2A phosphatase activator that dephosphorylates tau and stops memory impairment, is effective in the TMHT tau model (Corcoran et al., J. Clin. Neuroscience, 17: 1025-1033, 2010).

Decreased levels of p-tau in the brain are observed when long-term treatment with the compounds of the invention is associated with a general improvement in memory function as measured by the Morris Maze. obtain.

Other Embodiments The present invention is also described by the following numbered embodiments.

（式中、
Ｚ¹が、−ＯＲ⁷、−Ｎ（Ｒ¹⁰）Ｒ⁷、−ＳＲ⁷、または−Ｃ（Ｒ¹⁰）（Ｒ¹¹）Ｒ⁷であり；
Ｚ²が、−Ｎ＝または−Ｃ（Ｒ³）＝であり；
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるアミノであり、かつＲ⁴が、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の酸素、または１個の硫黄を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
各Ｒ⁵およびＲ⁶が、独立して、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｒ¹⁰が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ¹¹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキルであり、またはＲ¹⁰およびＲ¹¹が結合して、＝Ｏまたは＝Ｓを形成し；
Ｒ^mが、Ｈ、ハロゲン、任意選択的に置換されるＣ_1〜4アルキル、または任意選択的に置換されるＣ_1〜3アルコキシであり；
ここで、
Ｚ²がＣＲ³であり、Ｒ¹およびＲ²のそれぞれがＨであり、Ｒ³がＨであり、Ｒ⁴が、メチルまたはクロロであり、かつＲ⁵およびＲ⁶のそれぞれがクロロである場合、
Ｚ¹がメトキシでなく；
Ｚ²がＮであり、Ｒ⁵およびＲ⁶のそれぞれがクロロであり、Ｒ³がＨであり、Ｒ⁴が置換Ｃ_1〜6チオアルコキシである場合、
Ｚ¹が、シアノメトキシまたはアミノメトキシでなく；
Ｚ²がＣＲ³であり、Ｒ⁵およびＲ⁶のそれぞれがクロロであり、Ｒ³がＨであり、かつＲ⁴がハロゲンである場合、
Ｚ¹が、２−アミノ−２−オキソエトキシ、２−（Ｎ，Ｎ−ジエチルアミノ）エトキシ、メトキシ、またはベンジルオキシでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、Ｒ⁷およびＲ⁸が結合して、−ＣＨ₂−ＣＨ₂−を形成し、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁹が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく、
Ｒ⁵がメトキシであり、Ｒ⁶がメチルであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がエチルであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ⁷がメチルであり、Ｒ⁵がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ⁶がブロモでなく；
Ｒ⁵がクロロであり、Ｒ⁶がメトキシであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ⁷が、２−メトキシエチルまたはベンジルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ⁷がベンジルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁶がメチルである場合、
各Ｒ¹およびＲ²がＨであり；および
Ｒ³がＨであり、Ｚ¹が−ＯＲ⁷であり、かつ各Ｒ⁵およびＲ⁶がクロロである場合、
Ｒ⁷がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。 1. 1. Equation (I):

(During the ceremony,
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
Z ² is -N = or -C (R ³ ) =;
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkoxy, or C _{6 to 10} aryl optionally substituted, or R ³ and R ⁴ combined with the atom to which each is attached, one nitrogen, 1 It forms an optionally substituted 5- or 6-membered ring containing an optional oxygen, or 1 sulfur, where nitrogen is optionally substituted with R ⁹ ;
Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkcycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted Are C _1-3 alkalines substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, from nitrogen, oxygen, and sulfur. Form an arbitrarily substituted five- or six-membered ring containing one or two selected heteroatoms optionally;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or optionally substituted C _1-3 alkalil, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ are attached. To form = O or = S;
R ^m is H, halogen, optionally substituted C _1-4 alkyl, or optionally substituted C _1-3 alkoxy;
here,
When Z ² is CR ³ , each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro. ,
Z ¹ is not methoxy;
If Z ² is N, R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy.
Z ¹ is not cyanomethoxy or aminomethoxy;
If Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen.
Z ¹ is not 2-amino-2-oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy;
Formula (IIa): R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine. When forming a group represented by the formula (IIa),
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl,
When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
Formula (IIIa), where R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVb) :.

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to formulate (IVg), (IVh), (IVi), (IVj). , Or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
If each R ¹ and R ² is H; and R ³ is H, Z ¹ is -OR ⁷ , and each R ⁵ and R ⁶ is chloro.
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.

2. The compound of embodiment 1, wherein R ^m is H.

（式中、
各Ｒ¹およびＲ²が、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるアミノであり、Ｒ⁴が、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルキル、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の酸素、または１個の硫黄を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
各Ｒ⁵およびＲ⁶が、独立して、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
Ｚ¹が、−ＯＲ⁷、−Ｎ（Ｒ¹⁰）Ｒ⁷、−ＳＲ⁷、または−Ｃ（Ｒ¹⁰）（Ｒ¹¹）Ｒ⁷であり；
Ｒ¹⁰が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ¹¹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキルであり、またはＲ¹⁰およびＲ¹¹が結合して、＝Ｏまたは＝Ｓを形成し；
ここで、
Ｒ¹およびＲ²のそれぞれがＨであり、Ｒ³がＨであり、Ｒ⁴が、メチルまたはクロロであり、かつＲ⁵およびＲ⁶のそれぞれがクロロである場合、
Ｚ¹がメトキシでなく；
Ｒ⁵およびＲ⁶のそれぞれがクロロであり、Ｒ³がＨであり、かつＲ⁴がハロゲンである場合、
Ｚ¹が、２−アミノ−２−オキソエトキシ、２−（Ｎ，Ｎ−ジエチルアミノ）エトキシ、メトキシ、またはベンジルオキシでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、Ｒ⁷およびＲ⁸が結合して、−ＣＨ₂−ＣＨ₂−を形成し、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁹が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく、
Ｒ⁵がメトキシであり、Ｒ⁶がメチルであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がエチルであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ⁷がメチルであり、Ｒ⁵がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ⁶がブロモでなく；
Ｒ⁵がクロロであり、Ｒ⁶がメトキシであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ⁷が、２−メトキシエチルまたはベンジルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ⁷がベンジルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、Ｚ¹が−ＯＲ⁷であり、かつＲ³およびＲ⁴が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁶がメチルである場合、
各Ｒ¹およびＲ²がＨであり；および
Ｒ³がＨであり、Ｚ¹が−ＯＲ⁷であり、かつ各Ｒ⁵およびＲ⁶がクロロである場合、
Ｒ⁷がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。 3. 3. Equation (Ia):

(During the ceremony,
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, R ⁴ Are halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 ~ 6} thioalkyl, or C _6-10 aryls optionally substituted, or R ³ and R ⁴ are bonded together with the atom to which each is attached, one nitrogen, one It forms a optionally substituted 5- or 6-membered ring containing oxygen, or 1 sulfur, where nitrogen is optionally substituted with R ⁹ ;
Each R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkcycloalkyl, optionally substituted C _1-3 alkheterocyclyl, or optionally substituted Are C _1-3 alkalines substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded, from nitrogen, oxygen, and sulfur. Form an arbitrarily substituted five- or six-membered ring containing one or two selected heteroatoms optionally;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or optionally substituted C _1-3 alkalil, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ are attached. To form = O or = S;
here,
If R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro.
Z ¹ is not methoxy;
If each of R ⁵ and R ⁶ is chloro, R ³ is H, and R ⁴ is halogen, then
Z ¹ is not 2-amino-2-oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy;
Formula (IIa): R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine. When forming a group represented by the formula (IIa),
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl,
When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
Formula (IIIa), where R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVb) :.

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to formulate (IVg), (IVh), (IVi), (IVj). , Or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
If each R ¹ and R ² is H; and R ³ is H, Z ¹ is -OR ⁷ , and each R ⁵ and R ⁶ is chloro.
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.

（式中、
Ｒ¹およびＲ²のそれぞれが、独立して、Ｈまたは任意選択的に置換されるＣ_1〜3アルキルであり；
Ｒ³が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、または任意選択的に置換されるアミノであり、かつＲ⁴が、ハロゲン、シアノ、任意選択的に置換されるＣ_1〜6アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ_1〜6チオアルコキシ、または任意選択的に置換されるＣ_6〜10アリールであり、またはＲ³およびＲ⁴が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の硫黄、または１個の酸素を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、窒素が、Ｒ⁹で任意選択的に置換され；
Ｒ⁵およびＲ⁶のそれぞれが、独立して、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルコキシ、ハロゲン、またはＣＮであり；
Ｒ⁷が、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり、かつＲ⁸がＨであり；またはＲ⁷およびＲ⁸が、それぞれが結合される原子と一緒に、結合して、任意選択的に置換される五員または六員環を形成し；
Ｒ⁹が、Ｈ、任意選択的に置換されるＣ_1〜3アルキル、任意選択的に置換されるＣ_3〜8シクロアルキル、任意選択的に置換されるＣ_6〜10アリール、任意選択的に置換されるＣ_2〜9ヘテロアリール、任意選択的に置換されるＣ_2〜9ヘテロシクリル、任意選択的に置換されるＣ_1〜3アルクシクロアルキル、任意選択的に置換されるＣ_1〜3アルクヘテロシクリル、または任意選択的に置換されるＣ_1〜3アルカリールであり；
ここで、
Ｒ¹およびＲ²のそれぞれがＨであり、Ｒ³がＨであり、Ｒ⁴が、メチルまたはクロロであり、かつＲ⁵およびＲ⁶のそれぞれがクロロである場合、
Ｒ⁷がメチルでなく；
Ｒ⁵およびＲ⁶のそれぞれがクロロであり、Ｒ³がＨであり、かつＲ⁴がハロゲンである場合、
Ｒ⁷が、２−アミノ−２−オキソエチル、２−（Ｎ，Ｎ−ジエチルアミノ）エチル、メチル、またはベンジルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ⁷が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）−エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がブロモであり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｒ⁸がＨであり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、Ｒ⁷およびＲ⁸が結合して、−ＣＨ₂−ＣＨ₂−を形成し、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁹が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく；
Ｒ⁵がメトキシであり、Ｒ⁶がメチルであり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がエチルであり、かつＲ³およびＲ⁴が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ⁷がメチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ⁷が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ⁷がメチルであり、Ｒ⁵がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ⁶がブロモでなく；
Ｒ⁵がクロロであり、Ｒ⁶がメトキシであり、かつＲ³およびＲ⁴が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ¹もＲ²も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ⁷が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ⁷が、２−メトキシエチルまたはベンジルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ⁷が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ⁷が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ⁵およびＲ⁶がクロロであり、かつＲ³およびＲ⁴が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ⁷がベンジルでなく；
Ｒ⁵がクロロであり、Ｒ⁶がブロモであり、かつＲ³およびＲ⁴が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ⁷がメチルでなく；
Ｒ⁶がメチルである場合、
各Ｒ¹およびＲ²がＨであり；および
Ｒ³がＨであり、かつ各Ｒ⁵およびＲ⁶がクロロである場合、
Ｒ⁷がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。 4. Equation (Ib):

(During the ceremony,
Each of R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally;
R ³ is H, halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkoxy, or C _{6 to 10} aryl optionally substituted, or R ³ and R ⁴ combined with the atom to which each is attached, one nitrogen, 1 Forming an optionally substituted 5- or 6-membered ring containing an optional amount of sulfur or 1 oxygen, where nitrogen is optionally substituted with R ⁹ ;
Each of R ⁵ and R ⁶ is independently H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, halogen, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 arccycloalkyl, optionally substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkaline to be substituted with, and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atom to which each is attached and optionally substituted. Form a five- or six-membered ring;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted;
here,
If R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro.
R ⁷ is not methyl;
If each of R ⁵ and R ⁶ is chloro, R ³ is H, and R ⁴ is halogen, then
R ⁷ is not 2-amino-2-oxoethyl, 2- (N, N-diethylamino) ethyl, methyl, or benzyl;
R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are combined, formula (IIa):

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) -ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, R ⁸ is H, and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine to represent formula (IIa). When forming a group
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl;
When R ⁵ is methoxy, R ⁶ is methyl, and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are bound to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
R ⁷ is methyl, R ⁵ is chloro, and R ³ and R ⁴ are combined, formula (IIIa).

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVb):

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are bound to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
If each R ¹ and R ² is H; and if R ³ is H and each R ⁵ and R ⁶ is chloro.
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.

5. R ³ is H, halogen, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy, and R ⁴ is halogen, optionally substituted. C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _{1 to 6} thioalkyl, or optionally substituted C _6-10 aryl, or R ³ and R ⁴ are bonded together with the atoms to which they are bonded, optionally one nitrogen, one oxygen, or one sulfur. The compound of any one of embodiments 1 to 4, wherein an optionally substituted 5- or 6-membered ring is formed, wherein the nitrogen is optionally substituted with R ⁹ .

6. The compound of any one of embodiments 1-5, wherein R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form a five-membered ring that is optionally substituted.

7. The compound of any one of embodiments 1-5, wherein R ³ and R ⁴ combine to form a −CH ₂ CH ₂ CH ₂ − group.

8. Any one of embodiments 1-5, wherein R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one nitrogen. Two compounds.

9. The compound of embodiment 8 in which R ³ and R ⁴ combine to form the -N (R ⁹ ) -CH = CH- group.

10. The compound of embodiment 9, wherein R ⁹ is H.

11. Any one of embodiments 1-5, wherein R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur. Two compounds.

12. R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is H or optionally. The compound of any one of embodiments 1-5, which is a C _1-3 alkyl substituted with.

13. The compound of embodiment 12, wherein R ^13B is a C _1-3 alkyl optionally substituted.

14. The compound of embodiment 13, wherein R ^13B is -C (O) -R ^13C , where R ^13C is optionally substituted C _1-3 alkoxy or optionally substituted amino. ..

15. R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is H or -C (O). ) -R ^13C and R ^13C is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted amino, or optionally substituted The compound of any one of embodiments 1-5, which is a C _2-9 heterocyclyl that is substituted with respect to.

16. The compound of any one of embodiments 1-5, wherein R ⁴ is C _1-3 alkyl.

17. The compound of embodiment 16, wherein R ⁴ is methyl, ethyl, or isopropyl.

18. The compound of any one of embodiments 1-5, wherein R ⁴ is C _1-3 alkoxy.

19. The compound of embodiment 18, wherein R ⁴ is methoxy.

20. The compound of any one of embodiments 1-5, wherein R ⁴ is C _1-6 thioalkoxy optionally substituted.

21. The compound of embodiment 20, wherein R ⁴ is 4-amino-4-oxobutyl.

22. The compound of any one of embodiments 1-5, wherein R ⁴ is an amino that is optionally substituted.

23. The compound of embodiment 22, wherein R ⁴ is methyl amino.

24. The compound according to any one of embodiments 1 to 5, wherein R ⁴ is a halogen.

25. The compound of embodiment 24, wherein R ⁴ is chloro.

26. The compound of any one of embodiments 1-5 and 15-25, wherein R ³ is hydrogen or C _1-3 alkyl.

27. The compound of embodiment 26, wherein R ³ is hydrogen, methyl, or ethyl.

28. R ³ and R ⁴ combine to form −X ¹ −X ² −X ³⁻ , where
X ¹ is replaced with -S-, -O-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, -N (R ⁹ )-, -N =, H, or optionally. C _1-3 alkyl;
X ² is absent or-(CR ¹⁷ R ¹⁸ ) _n-, -S-, -O-, -N =, -N (R ⁹ )-, -C (R ¹⁹ ) =, = N- , = C (R ²⁰ )-or = C (R ²¹ ) -C (R ²² ) =;
X ³ is optionally replaced with − (CR ¹⁴ R ¹⁵ ) −, −S−, −O−, −N (R ⁹ ) −, = N−, = C (R ²³ ) −, halogen. C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;
Each R ¹⁴ and R ¹⁵ is an independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form = O or = S;
Each R ¹⁷ and R ¹⁸ are independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form = O or = S;
Each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are independently H, or C _1-3 alkyl optionally substituted;
n is 1 or 2;
Here, if X ² does not exist,
Any of embodiments 1-5, wherein the chain of atoms −X ¹ −X ² −X ³⁻ comprises one or less heteroatoms, the heteroatoms being selected from the group consisting of nitrogen, oxygen, and sulfur. One compound.

29. X ¹ is − (CR ¹⁴ R ¹⁵ ) −, −C (R ¹⁶ ) =, −N (R ⁹ ) −, −N =, or C _1-3 alkyl optionally substituted. The compound of form 28.

30. The compound of embodiment 29, wherein X ¹ is − (CR ¹⁴ R ¹⁵ ) −.

31. The compound of embodiment 30, wherein each R ¹⁴ and R ¹⁵ is H.

32. The compound of embodiment 29, wherein X ¹ is −C (R ¹⁶ ) =.

33. The compound of embodiment 32, wherein R ¹⁶ is H.

34. The compound of embodiment 29, wherein X ¹ is −N (R ⁹ ) −.

35. The compound of embodiment 34, wherein R ⁹ is H or a C _1-3 alkyl optionally substituted.

36. The compound of embodiment 35, wherein R ⁹ is hydrogen, methyl, or ethyl.

37. The compound of embodiment 29, wherein X ¹ is −N =.

38. The compound of embodiment 29, wherein X ¹ is a C _1-3 alkyl optionally substituted.

39. X ² does not exist, or-(CH ₂ ) _n- , -N (R ⁹ )-, -C (H) =, = C (R ²⁰ )-, or = C (H) -C (H) ) =, Any one compound of embodiments 28-37.

40. The compound of embodiment 39, wherein X ² is −C (H) =.

41. The compound of embodiment 39, wherein X ² is −N (R ⁹ ) −.

42. The compound of embodiment 41, wherein R ⁹ is H.

43. The compound of embodiment 41, wherein R ⁹ is a C _1-3 alkyl optionally substituted.

44. The compound of embodiment 43, wherein R ⁹ is -C (O) -N (H) -Et.

45. The compound of embodiment 39, wherein X ² is = C (R ²⁰ ) −.

46. The compound of embodiment 45, wherein R ²⁰ is a C _1-3 alkyl optionally substituted.

47. The compound of embodiment 39 in which X ² is absent.

48. X ³ is -CH _2- , -S-, = C (H)-, -N (R ⁹ )-, halogen, optionally substituted C _1-3 alkyl, optionally substituted One of the compounds of embodiments 28-37 and 39-47, which are C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, optionally substituted C _6-10 aryl. ..

49. The compound of embodiment 48, wherein X ³ is −CH ₂₋ .

50. The compound of embodiment 48, wherein X ³ is −S−.

51. The compound of embodiment 48, wherein X ³ is = C (H) −.

52. The compound of embodiment 48, wherein X ³ is −N (R ⁹ ) −.

53. X ³ is halogen, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted C _1-6 thioalkoxy, or optionally substituted The compound of embodiment 48, which is C _6-10 aryl substituted with.

54. The compound of any one of embodiments 1-53, wherein each of R ⁵ and R ⁶ is an independently halo or optionally substituted C _1-3 alkyl.

55. The compound of embodiment 54, wherein each R ⁵ and R ⁶ is halo.

56. The compound of embodiment 55, wherein each R ⁵ and R ⁶ is chloro.

57. R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. The compound of any one of embodiments 1-56 that forms a five- or six-membered ring.

58. R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. The compound of any one of embodiments 1-56 that forms a five- or six-membered saturated ring.

59. Five of which R ⁷ and R ⁸ are optionally bonded together with the atoms to which they are bonded, optionally containing one or two heteroatoms selected from nitrogen and oxygen. The compound of any one of embodiments 1-56 that forms a member or six-membered ring.

60. The compound of any one of embodiments 1-56, wherein R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded to form a five-membered ring that is optionally substituted.

61. The compound of any one of embodiments 1-56, wherein R ⁷ and R ⁸ are bonded together with the atoms to which they are bonded to form a saturated five-membered ring that is optionally substituted.

62. The compound of any one of embodiments 1-56, wherein R ⁷ and R ⁸ combine to form a −CH ₂ CH ₂ − group.

63. The compound of any one of embodiments 1-56, wherein R ⁷ is a C _1-3 alkyl optionally substituted.

64. The compound of embodiment 63, wherein R ⁷ is methyl.

65. R ⁷ is − (CH ₂ ) _k −N (R ²⁴ ) R ²⁵ , k is 2 or 3, and each R ²⁴ and R ²⁵ is independently replaced by H or optionally. The compound of embodiment 63, which is C _1-3 alkyl.

66. The compound of embodiment 65, wherein k is 2.

67. The compound of embodiment 65 or 66, wherein each R ²⁴ and R ²⁵ is a C _1-3 alkyl that is independently and optionally substituted.

68. The compound of any one of embodiments 65-67, wherein each R ²⁴ and R ²⁵ is methyl.

69. R ⁷ and R ⁸ form the group −Y ¹ −Y ² −, where:
Y ¹ is − (CR ²⁶ R ²⁷ ) _m − or optionally substituted C _1-3 alkyl, optionally substituted C _1-3 archeterocyclyl, optionally substituted C _{1 ~ 3} alkcycloalkyl, or C _1-3 alkaline, optionally substituted;
Y ² is-(CR ²⁶ R ²⁷ )-or H; where
One compound of any one of embodiments 1-56, where each R ²⁶ and R ²⁷ is an independently H or optionally substituted C _1-3 alkyl; and m is 1 or 2. ..

70. Z ¹ and R ⁸ combine to form −Z ³ −Y ¹ −Y ² −, where
Z ³ is -O-, -N (R ¹⁰ )-, -N =, -S-, or-(CR ¹⁴ R ¹⁵ )-;
Y ¹ is -O-, -N (R ¹⁰ )-, -S-,-(CR ²⁶ R ²⁷ ) _m- , -C (R ²⁰ ) =, = C (R ²⁰ )-, = C (R) ^{21) -C (R 22) =} , C 1~3 alkyl, C _{1 to 3} alkheterocyclyl, C _{1 to 3} alkcycloalkyl which is optionally substituted is optionally substituted is optionally substituted Alkyl, or C _1-3 alkaline, optionally substituted;
Y ² is -O-, -S-, -N (R ¹⁰ )-,-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, = N-, or H;
here,
Each R ²⁰ , R ²¹ , and R ²² are C _1-3 alkyls that are independently substituted with H or optionally;
Each R ²⁶ and R ²⁷ is an independently H or optionally substituted C _1-3 alkyl, or R ²⁶ and R ²⁷ combine to form = O or = S;
m is 1 or 2;
Here, if Y ² is H,
The compound of any one of embodiments 1-5, wherein the chain of atoms −Z ^3- Y ¹ −Y ² − contains no more than two heteroatoms, the heteroatoms being selected from nitrogen, oxygen, and sulfur. ..

71. The compound of embodiment 70, wherein Z ³ is −O−.

72. Y ¹ is − (CR ²⁶ R ²⁷ ) _m − or optionally substituted C _1-3 alkyl, optionally substituted C _1-3 archeterocyclyl, optionally substituted C ₁ The compound of embodiment 69 or 71, which is _{~ 3} alkcycloalkyl, or C _1-3 alkaline, which is optionally substituted.

73. The compound of any one of embodiments 69-72, wherein Y ¹ is − (CR ²⁶ R ²⁷ ) _m − or optionally substituted C _1-3 alkyl.

74. The compound of any one of embodiments 69-73, wherein Y ² is − (CR ²⁶ R ²⁷ ) − or H.

75. The compound of any one of embodiments 69-74, wherein Y ² is − (CR ²⁶ R ²⁷ ) −.

76. The compound of any one of embodiments 69-75, wherein R ²⁶ is H.

77. The compound of any one of embodiments 69-76, wherein R ²⁷ is H.

78. The compound of any one of embodiments 69-77, wherein m is 1.

79. The compound of any one of embodiments 69-78, wherein Y ¹ is a C _1-3 alkyl optionally substituted.

80. The compound of embodiment 79, wherein Y ¹ is methyl.

81. Y ¹ is − (CH ₂ ) _k −N (R ²⁴ ) R ²⁵ , where k is 2 or 3, and each R ²⁴ and R ²⁵ is independently H or optional. The compound of embodiment 80, which is a C _1-3 alkyl substituted with.

82. The compound of embodiment 81, wherein k is 2.

83. The compound of embodiment 81 or 82, wherein each R ²⁴ and R ²⁵ is a C _1-3 alkyl that is independently and optionally substituted.

84. The compound of any one of embodiments 81-83, wherein each R ²⁴ and R ²⁵ is methyl.

85. The compound of any one of embodiments 1-84, wherein each R ¹ and R ² is H.

、またはその薬学的に許容できる塩。 86. Compound:

, Or its pharmaceutically acceptable salt.

で表される、実施形態８４の化合物、またはその薬学的に許容できる塩。 87. formula:

The compound of embodiment 84, or a pharmaceutically acceptable salt thereof, represented by.

88. A pharmaceutical composition comprising any one of the compounds of embodiments 1-87, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier or excipient.

89. Orally, sublingually, orally, percutaneously, intradermally, intramuscularly, parenterally, intravenously, intraarterial, intracranial, subcutaneously, intraorbitally, intraventricularly , The pharmaceutical composition of embodiment 88, formulated for intrathecal, intraperitoneal, intranasal, inhalation, and topical administration.

90. The pharmaceutical composition of embodiment 89, which is formulated for oral administration.

91. A method of treating a mammalian disease caused by the action of heat shock protein 90 (Hsp90), wherein an effective amount of any one compound of embodiments 1-87 or a pharmaceutically acceptable salt thereof or embodiment thereof. A method comprising the step of administering 88 pharmaceutical compositions to a mammal.

92. The method of embodiment 91, wherein the disease is a neurodegenerative disease.

93. The method of embodiment 92, wherein the neurodegenerative disease is tauopathy.

94. If the neurodegenerative disease is Alzheimer's disease, Huntington's disease, progressive supraclavicular paralysis, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia, practice The method of form 92 or 93.

95. The method of embodiment 94, wherein the neurodegenerative disease is Alzheimer's disease.

96. The method of embodiment 91, wherein the disease is a proliferative disease.

97. The method of embodiment 96, wherein the proliferative disease is cancer.

98. Cancers include acute myelogenous leukemia, gastrointestinal stromal tumor, gastric cancer, glioma, neuroblastoma, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, kidney cancer, small cells In lung cancer, acute chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, recurrent multiple myeloma, refractory multiple myeloma, myelogenous disease, pancreatic cancer, small bowel cancer, or solid tumor A method of embodiment 97.

99. A method of treating an infectious disease in a mammal, wherein an effective amount of any one of the compounds of embodiments 1-87 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 88 is administered to the mammal. A method that includes a step.

100. The method of embodiment 99, wherein the infectious disease is a viral infection.

101. Viral infectious diseases include herpesvirus family (Herpesviridae), polyomavirus family (Polyomaviridae), poxvirus family (Poxviridae), leovirus family (Reoviridae), Birnaviridae (Birnaviridae), picornavirus. Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramixyviridae, Paramoxyviridae, Bunyaviridae, Bunyaviridae The method of embodiment 100, wherein the infection is caused by a virus of a family selected from the group consisting of the family Flaviviridae, the family Retrovirus, and the family Hepadnaviridae.

102. The virus of the herpesviridae family (Herpesviridae) is herpes simplex virus type 1, herpes simplex virus type 2, herpes herpesvirus type 5, Kaposi sarcoma-related herpesvirus, varicella zoster virus, or Epstein bar virus, embodiment 101. the method of.

103. The method of embodiment 101, wherein the virus of the Polyomaviridae family is SV40.

104. The method of embodiment 101, wherein the Poxviridae virus is a vaccinia virus.

105. The method of embodiment 101, wherein the virus of the Reoviridae family is rotavirus.

106. The method of embodiment 101, wherein the virus of the Birnaviridae family is an infectious bursal disease virus.

107. The method of embodiment 101, wherein the Picornaviridae virus is a poliovirus, rhinovirus, or coxsackievirus.

108. The method of embodiment 101, wherein the Flaviviridae virus is hepatitis C virus or dengue virus.

109. The method of embodiment 101, wherein the Arenaviridae virus is a lymphocytic choriomyticitis virus.

110. The method of embodiment 101, wherein the virus of the Hepeviridae family is a hepatitis E virus.

111. The method of embodiment 101, wherein the Rhabdoviridae virus is a vesicular stomatitis virus.

112. The method of embodiment 101, wherein the virus of the Paramyxoviridae family is human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus.

113. The method of embodiment 101, wherein the virus of the Bunyaviridae family is a lacrosse virus.

114. The method of embodiment 101, wherein the virus of the Orthomyxoviridae family is influenza A virus.

115. The method of embodiment 101, wherein the virus of the Filoviridae family is an Ebola virus.

116. The method of embodiment 101, wherein the virus of the retrovirus family (Retroviridae) is HTLV1 or HIV1.

117. The method of embodiment 101, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

118. The method of embodiment 99, wherein the infectious disease is a fungal infection.

119. Method 118, wherein the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or a Pneumocystis jiroveci infection.

120. The method of embodiment 99, wherein the infection is a bacterial infection.

121. The method of embodiment 120, wherein the bacterial infection is an acid-fast bacillus infection or anthrax infection.

122. The method of embodiment 120, wherein the bacterial infection is bacterial pneumonia.

123. The method of embodiment 91, wherein the disease is an inflammatory or autoimmune disease.

124. The method of embodiment 123, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

125. The method of embodiment 91, wherein the disease is cardiovascular disease.

126. The method of embodiment 125, wherein the cardiovascular disease is atherosclerosis or cardiomyopathy.

127. The method of embodiment 91, wherein the disease is allergic.

128. The compound is orally, sublingually, orally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranial, subcutaneously, intraorbitally. The method of any one of embodiments 91-127, which is administered intraventricularly, intrathecally, intraperitoneally, intranasally, by inhalation, and topically.

129. The method of embodiment 128, wherein the compound is administered orally.

130. The method of any one of embodiments 91-129, wherein the mammal is a human.

131. The compound is orally, sublingually, orally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranial, subcutaneously, intraorbitally. The method of any one of embodiments 91-130, which is administered intraventricularly, intrathecally, intraperitoneally, intranasally, by inhalation, and topically.

132. The method of embodiment 131, wherein the compound is administered orally.

133. The method of any one of embodiments 91-132, wherein the mammal is a human.

134. A compound for use in treating a mammalian disease caused by the action of heat shock protein 90 (Hsp90), any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof. ..

135. The compound of embodiment 134, wherein the disease is a neurodegenerative disease.

136. The compound of embodiment 135, wherein the neurodegenerative disease is tauopathy.

137. If the neurodegenerative disease is Alzheimer's disease, Huntington's disease, progressive supraclavicular paralysis, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia, practice Compound of form 134 or 135.

138. The compound of embodiment 137, wherein the neurodegenerative disease is Alzheimer's disease.

139. The compound of embodiment 134, wherein the disease is a proliferative disease.

140. The compound of embodiment 139, wherein the proliferative disease is cancer.

141. Cancers include acute myelogenous leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, kidney cancer, small cell lung cancer, acute chronic myelogenous leukemia, The compound of embodiment 140, which is leukemia, lymphoproliferative disorder, metastatic melanoma, recurrent multiple myeloma, refractory multiple myeloma, myelogenous disorder, pancreatic cancer, small bowel cancer, or solid tumor.

142. The compound of embodiment 134, wherein the disease is an infectious disease.

143. The compound of embodiment 142, wherein the infectious disease is a viral infection.

144. Viral infectious diseases include herpesvirus family (Herpesviridae), polyomavirus family (Polyomaviridae), poxvirus family (Poxviridae), leovirus family (Reoviridae), Birnaviridae family (Birnaviridae) Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramixyviridae, Paramoxyviridae, Buniaviridae, Buniaviridae, Bunyaviridae The compound of embodiment 143, which is an infection caused by a virus of a family selected from the group consisting of the family Flaviviridae, the family Retrovirus, and the family Hepadnaviridae.

145. The virus of the herpesviridae family (Herpesviridae) is herpes simplex virus type 1, herpes simplex virus type 2, herpes herpesvirus type 5, Kaposi sarcoma-related herpesvirus, varicella-zoster virus, or Epstein bar virus, embodiment 144. Compound.

146. The compound of embodiment 144, wherein the virus of the family Polyomaviridae is SV40.

147. The compound of embodiment 144, wherein the virus of the Poxvirus family is a vaccinia virus.

148. The compound of embodiment 144, wherein the virus of the Reoviridae family is rotavirus.

149. The compound of embodiment 144, wherein the virus of the Birnaviridae family is an infectious bursal disease virus.

150. The compound of embodiment 144, wherein the virus of the Picornavirus family is a poliovirus, rhinovirus, or coxsackievirus.

141. The compound of embodiment 144, wherein the Flaviviridae virus is hepatitis C virus or dengue virus.

152. The compound of embodiment 144, wherein the virus of the Arenaviridae family is lymphocytic choriomyticitis virus.

153. The compound of embodiment 144, wherein the virus of the Hepeviridae family is hepatitis E virus.

154. The compound of embodiment 144, wherein the virus of the Rhabdoviridae family is the vesicular stomatitis virus.

155. The compound of embodiment 144, wherein the virus of the Paramyxoviridae family is human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus.

156. The compound of embodiment 144, wherein the virus of the Bunyaviridae family is lacrosse virus.

157. The compound of embodiment 144, wherein the virus of the Orthomyxoviridae is an influenza A virus.

158. The compound of embodiment 144, wherein the virus of the Filoviridae family is Ebolavirus.

159. The compound of embodiment 144, wherein the virus of the retrovirus family (Retroviridae) is HTLV1 or HIV1.

160. The compound of embodiment 144, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

161. The compound of embodiment 134, wherein the infectious disease is a fungal infection.

162. Embodiment 16 where the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or a Pneumocystis jiroveci infection.

163. The compound of embodiment 134, wherein the infectious disease is a bacterial infection.

165. The compound of embodiment 163, wherein the bacterial infection is an acid-fast bacillus infection or anthrax infection.

166. The compound of embodiment 163, wherein the bacterial infection is bacterial pneumonia.

167. The compound of embodiment 134, wherein the disease is an inflammatory or autoimmune disease.

168. The compound of embodiment 167, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

169. The compound of embodiment 134, wherein the disease is cardiovascular disease.

170. The compound of embodiment 169, wherein the cardiovascular disease is atherosclerosis or cardiomyopathy.

171. The compound of embodiment 170, wherein the disease is allergic.

172. The use of a compound in the manufacture of a drug for treating a mammalian disease caused by the action of heat shock protein 90 (Hsp90), wherein the compound is any one of the compounds of embodiments 1-87 or pharmaceuticals thereof. Is an acceptable salt for use.

173. Use of a compound for treating a mammalian disease caused by the action of heat shock protein 90 (Hsp90), wherein the compound is any one of embodiments 1-87 or a pharmaceutically acceptable salt thereof. Is used.

174. Use of embodiment 172 or 173, wherein the disease is a neurodegenerative disease.

175. Use of embodiment 174, wherein the neurodegenerative disease is tauopathy.

176. If the neurodegenerative disease is Alzheimer's disease, Huntington's disease, progressive supraclavicular paralysis, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia, practice Use of form 174 or 175.

177. Use of embodiment 176, wherein the neurodegenerative disease is Alzheimer's disease.

178. Use of embodiment 172 or 173, wherein the disease is a proliferative disease.

179. Use of embodiment 178, wherein the proliferative disease is cancer.

180. Cancers include acute myelogenous leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, kidney cancer, small cell lung cancer, acute chronic myelogenous leukemia, Use of embodiment 179, which is leukemia, lymphoproliferative disorder, metastatic melanoma, recurrent multiple myeloma, refractory multiple myeloma, myelogenous disorder, pancreatic cancer, small bowel cancer, or solid tumor.

181. Use of a compound in the manufacture of a drug for treating an infectious disease or for treating an infectious disease, wherein the compound is any one of embodiments 1-87.

182. Use of Embodiment 181 where the infectious disease is a viral infection.

183. Viral infectious diseases include herpesvirus family (Herpesviridae), polyomavirus family (Polyomaviridae), poxvirus family (Poxviridae), leovirus family (Reoviridae), Birnaviridae (Birnaviridae), picornavirus. Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramixyviridae, Paramoxyviridae, Buniaviridae, Buniaviridae, Bunyaviridae Use of embodiment 182, which is an infectious disease caused by a family of viruses selected from the group consisting of the family Flaviviridae, the family Retrovirus, and the family Hepadnaviridae.

184. The virus of the herpesvirus family (Herpesviridae) is herpes simplex virus type 1, herpes simplex virus type 2, herpes herpesvirus type 5, Kaposi sarcoma-related herpesvirus, varicella-zoster virus, or Epstein bar virus, embodiment 183. Use of.

185. Use of embodiment 183, wherein the virus of the Polyomaviridae family is SV40.

186. Use of embodiment 183, wherein the Poxviridae virus is a vaccinia virus.

187. Use of embodiment 183, wherein the virus of the Reoviridae family is rotavirus.

188. Use of embodiment 183, wherein the virus of the Birnaviridae family is an infectious bursal disease virus.

189. Use of embodiment 183, wherein the Picornaviridae virus is a poliovirus, rhinovirus, or coxsackievirus.

190. Use of embodiment 183, wherein the Flaviviridae virus is hepatitis C virus or dengue virus.

191. Use of embodiment 183, wherein the virus of the Arenaviridae is a lymphocytic choriomyticitis virus.

192. Use of embodiment 183, wherein the virus of the Hepeviridae family is a hepatitis E virus.

193. Use of embodiment 183, wherein the Rhabdoviridae virus is a vesicular stomatitis virus.

194. Use of embodiment 183, wherein the virus of the Paramyxoviridae family is human parainfluenza virus type 2, human parainfluenza virus type 3, SV5, SV41, measles virus, or Sendai virus.

195. Use of embodiment 183, wherein the virus of the Bunyaviridae family is a lacrosse virus.

196. Use of embodiment 183, wherein the Orthomyxoviridae virus is influenza A virus.

197. Use of embodiment 183, wherein the virus of the Filoviridae family is the Ebola virus.

198. Use of embodiment 183, wherein the virus of the retrovirus family (Retroviridae) is HTLV1 or HIV1.

199. Use of embodiment 183, wherein the virus of the Hepadnaviridae family is hepatitis B virus.

200. Use of embodiment 172 or 173, wherein the infection is a fungal infection.

201. Use of Embodiment 200, wherein the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or a Pneumocystis jiroveci infection.

202. Use of embodiment 172 or 173, wherein the infection is a bacterial infection.

203. Use of embodiment 202, wherein the bacterial infection is an acid-fast bacillus infection or anthrax infection.

204. Use of Embodiment 203, wherein the bacterial infection is bacterial pneumonia.

205. Use of embodiment 172 or 173, wherein the disease is an inflammatory or autoimmune disease.

206. Use of embodiment 205, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.

207. Use of embodiment 172 or 173, wherein the disease is cardiovascular disease.

208. Use of embodiment 207, wherein the cardiovascular disease is atherosclerosis cardiomyopathy.

209. Use of embodiment 172 or 173, wherein the disease is allergic.

210. Compounds are oral, sublingual, oral, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intrathecal, intraperitoneal, intranasal, inhalation Use of any one of the compounds of embodiments 134-171 or any one of embodiments 172-209, which is formulated for administration by a route selected by and from the topical group.

211. The compound or use of embodiment 128, wherein the compound is formulated for oral administration.

212. A method of inhibiting Hsp90, comprising contacting the cells with any one of the compounds of embodiments 1-87 or a pharmaceutically acceptable salt thereof.

213. The method of embodiment 212, wherein the cells are in vitro.

214. A compound for use in inhibiting Hsp90, which is any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof.

215. Use of a compound for inhibiting Hsp90, wherein the compound is any one of the compounds of embodiments 1-87 or a pharmaceutically acceptable salt thereof.

216. (I) With any one of the pharmaceutical compositions of embodiments 88-90;
(Ii) A kit containing instructions for use of the pharmaceutical composition of (i) for treating a mammalian disease caused by the action of Hsp90.

As much as all publications, patents, and patent applications described herein are indicated by reference to each independent publication or patent application specifically and individually. Incorporated herein by reference.

Although the invention has been described in the context of its particular embodiment, further modifications are possible, and the present application is generally any modification, use, or use of the invention in accordance with the principles of the invention. The modifications are intended to include such deviations from the present disclosure, which are within the bounds of known or customary practice in the art to which the present invention belongs, to the essential features described above. It may be applied and will be understood to be in accordance with the claims.

（式中、
Ｚ ¹ が、−ＯＲ ⁷ 、−Ｎ（Ｒ ¹⁰ ）Ｒ ⁷ 、−ＳＲ ⁷ 、または−Ｃ（Ｒ ¹⁰ ）（Ｒ ¹¹ ）Ｒ ⁷ であり；
Ｚ ² が、−Ｃ（Ｒ ³ ）＝または−Ｎ＝であり；
各Ｒ ¹ およびＲ ² が、独立して、Ｈ、任意選択的に置換されるＣ _1〜3 アシル、または任意選択的に置換されるＣ _1〜3 アルキルであり；
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、硫黄、酸素、および窒素からなる群から選択される１〜３個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、前記窒素が、Ｒ ⁹ で任意選択的に置換され、またはＲ ³ が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、または任意選択的に置換されるアミノであり、かつＲ ⁴ が、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ _1〜6 チオアルコキシ、または任意選択的に置換されるＣ _6〜10 アリールであり；
Ｒ ⁵ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁶ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁷ およびＲ ⁸ が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員、六員、または七員環を形成し；またはＲ ⁷ が、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり、かつＲ ⁸ がＨであり；
Ｒ ⁹ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _3〜8 シクロアルキル、任意選択的に置換されるＣ _6〜10 アリール、任意選択的に置換されるＣ _2〜9 ヘテロアリール、任意選択的に置換されるＣ _2〜9 ヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり；
Ｒ ¹⁰ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _3〜8 シクロアルキル、任意選択的に置換されるＣ _6〜10 アリール、任意選択的に置換されるＣ _2〜9 ヘテロアリール、任意選択的に置換されるＣ _2〜9 ヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり、かつＲ ¹¹ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキルであり、またはＲ ¹⁰ およびＲ ¹¹ が結合して、＝Ｏまたは＝Ｓを形成し；および
Ｒ ^m が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜4 アシル、任意選択的に置換されるＣ _1〜4 アルキル、または任意選択的に置換されるＣ _1〜3 アルコキシであり；
ここで、
Ｚ ² がＣＲ ³ であり、Ｒ ¹ およびＲ ² のそれぞれがＨであり、Ｒ ³ がＨであり、Ｒ ⁴ が、メチルまたはクロロであり、かつＲ ⁵ およびＲ ⁶ のそれぞれがクロロである場合、
Ｚ ¹ がメトキシでなく；
Ｚ ² がＮであり、Ｒ ⁵ およびＲ ⁶ のそれぞれがクロロであり、Ｒ ³ がＨであり、Ｒ ⁴ が置換Ｃ _1〜6 チオアルコキシである場合、
Ｚ ¹ が、シアノメトキシまたはアミノメトキシでなく；
Ｚ ² がＣＲ ³ であり、Ｒ ⁵ およびＲ ⁶ のそれぞれがクロロであり、Ｒ ³ がＨであり、かつＲ ⁴ がハロゲンである場合、
Ｚ ¹ が、２−アミノ−２−オキソエトキシ、２−（Ｎ，Ｎ−ジエチルアミノ）エトキシ、メトキシ、またはベンジルオキシでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ ⁷ が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、Ｒ ⁷ およびＲ ⁸ が結合して、−ＣＨ ₂ −ＣＨ ₂ −を形成し、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁹ が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく、
Ｒ ⁵ がメトキシであり、Ｒ ⁶ がメチルであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がエチルであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ ⁷ が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ ⁷ がメチルであり、Ｒ ⁵ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ ⁶ がブロモでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がメトキシであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ ¹ もＲ ² も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ ⁷ が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−メトキシエチルまたはベンジルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ ⁷ がベンジルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁶ がメチルである場合、
各Ｒ ¹ およびＲ ² がＨであり；および
Ｒ ³ がＨであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつ各Ｒ ⁵ およびＲ ⁶ がクロロである場合、
Ｒ ⁷ がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。
［実施形態２］
Ｒ ^m がＨである、実施形態１に記載の化合物。
［実施形態３］
式（Ｉａ）：

（式中、
各Ｒ ¹ およびＲ ² が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり；
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、硫黄、酸素、および窒素からなる群から選択される１〜３個のヘテロ原子を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、前記窒素が、Ｒ ⁹ で任意選択的に置換され、またはＲ ³ が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、または任意選択的に置換されるアミノであり、かつＲ ⁴ が、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ _1〜6 チオアルキル、または任意選択的に置換されるＣ _6〜10 アリールであり；
Ｒ ⁵ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁶ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁷ およびＲ ⁸ が、それぞれが結合される原子と一緒に、結合して、窒素、酸素、および硫黄から選択される１個または２個のヘテロ原子を任意選択的に含む任意選択的に置換される五員、六員、または七員環を形成し；またはＲ ⁷ が、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり、かつＲ ⁸ がＨであり；
Ｒ ⁹ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _3〜8 シクロアルキル、任意選択的に置換されるＣ _6〜10 アリール、任意選択的に置換されるＣ _2〜9 ヘテロアリール、任意選択的に置換されるＣ _2〜9 ヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり；
Ｚ ¹ が、−ＯＲ ⁷ 、−Ｎ（Ｒ ¹⁰ ）Ｒ ⁷ 、−ＳＲ ⁷ 、または−Ｃ（Ｒ ¹⁰ ）（Ｒ ¹¹ ）Ｒ ⁷ であり；および
Ｒ ¹⁰ が、Ｈ、任意選択的に置換されるＣ _1〜3 アシル、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _3〜8 シクロアルキル、任意選択的に置換されるＣ _6〜10 アリール、任意選択的に置換されるＣ _2〜9 ヘテロアリール、任意選択的に置換されるＣ _2〜9 ヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり、かつＲ ¹¹ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキルであり、またはＲ ¹⁰ およびＲ ¹¹ が結合して、＝Ｏまたは＝Ｓを形成し；
ここで、
Ｒ ¹ およびＲ ² のそれぞれがＨであり、Ｒ ³ がＨであり、Ｒ ⁴ が、メチルまたはクロロであり、かつＲ ⁵ およびＲ ⁶ のそれぞれがクロロである場合、
Ｚ ¹ がメトキシでなく；
Ｒ ⁵ およびＲ ⁶ のそれぞれがクロロであり、Ｒ ³ がＨであり、かつＲ ⁴ がハロゲンである場合、
Ｚ ¹ が、２−アミノ−２−オキソエトキシ、２−（Ｎ，Ｎ−ジエチルアミノ）エトキシ、メトキシ、またはベンジルオキシでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ ⁷ が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、Ｒ ⁷ およびＲ ⁸ が結合して、−ＣＨ ₂ −ＣＨ ₂ −を形成し、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁹ が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく、
Ｒ ⁵ がメトキシであり、Ｒ ⁶ がメチルであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がエチルであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ ⁷ が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ ⁷ がメチルであり、Ｒ ⁵ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ ⁶ がブロモでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がメトキシであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ ¹ もＲ ² も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ ⁷ が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−メトキシエチルまたはベンジルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ ⁷ がベンジルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁶ がメチルである場合、
各Ｒ ¹ およびＲ ² がＨであり；および
Ｒ ³ がＨであり、Ｚ ¹ が−ＯＲ ⁷ であり、かつ各Ｒ ⁵ およびＲ ⁶ がクロロである場合、
Ｒ ⁷ がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。
［実施形態４］
式（Ｉｂ）：

（式中、
Ｒ ¹ およびＲ ² のそれぞれが、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり；
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の硫黄、または１個の酸素を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、前記窒素が、Ｒ ⁹ で任意選択的に置換され、またはＲ ³ が、Ｈ、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、または任意選択的に置換されるアミノであり、かつＲ ⁴ が、ハロゲン、シアノ、任意選択的に置換されるＣ _1〜6 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ _1〜6 チオアルコキシ、または任意選択的に置換されるＣ _6〜10 アリールであり；
Ｒ ⁵ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁶ が、ハロゲン、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、またはＣＮであり；
Ｒ ⁷ が、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり、かつＲ ⁸ がＨであり；またはＲ ⁷ およびＲ ⁸ が、それぞれが結合される原子と一緒に、結合して、任意選択的に置換される五員、六員、または七員環を形成し；および
Ｒ ⁹ が、Ｈ、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _3〜8 シクロアルキル、任意選択的に置換されるＣ _6〜10 アリール、任意選択的に置換されるＣ _2〜9 ヘテロアリール、任意選択的に置換されるＣ _2〜9 ヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、または任意選択的に置換されるＣ _1〜3 アルカリールであり；
ここで、
Ｒ ¹ およびＲ ² のそれぞれがＨであり、Ｒ ³ がＨであり、Ｒ ⁴ が、メチルまたはクロロであり、かつＲ ⁵ およびＲ ⁶ のそれぞれがクロロである場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁵ およびＲ ⁶ のそれぞれがクロロであり、Ｒ ³ がＨであり、かつＲ ⁴ がハロゲンである場合、
Ｒ ⁷ が、２−アミノ−２−オキソエチル、２−（Ｎ，Ｎ−ジエチルアミノ）エチル、メチル、またはベンジルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）：

で表される基を形成する場合、
Ｒ ⁷ が、メチル、エチル、ｎ−プロピル、２−（Ｎ−ピラゾリル）エチル、２−（Ｎ−イミダゾリル）エチル、３−ヒドロキシプロピル、シアノメチル、２−クロロエチル、２−ヒドロキシエチル、２−オキソ−プロピル、２−（Ｎ，Ｎ−ジメチルアミノ）−エチル、ジフルオロメチル、または２−（ｔ−ブチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がブロモであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｒ ⁸ がＨであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ が、メチル、２−（Ｎ−イミダゾリル）エチル、メトキシメチル、２−（Ｎ−ピラゾリル）エチル、２−（３−メチルピラゾール−１−イル）エチル、２−ピリジル−メチル、１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル−メチル、２−ピリミジニルメチル、イミダゾール−２−イル−メチル、５−メチル−イソオキサゾール−３−イル−メチル、４−メチル−イミダゾール−５−イル−メチル、または３−メチル−１，２，４−オキサジアゾール−５−イル−メチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、Ｒ ⁷ およびＲ ⁸ が結合して、−ＣＨ ₂ −ＣＨ ₂ −を形成し、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁹ が、エトキシカルボニル、シクロブチルアミノカルボニル、またはシクロブタジエニルアミノカルボニルでなく；
Ｒ ⁵ がメトキシであり、Ｒ ⁶ がメチルであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がエチルであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩａ）で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩｂ）または（ＩＩｃ）

で表される基を形成する場合、
Ｒ ⁷ が、メチルまたは２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
Ｒ ⁷ がメチルであり、Ｒ ⁵ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩａ）

で表される基を形成する場合、
Ｒ ⁶ がブロモでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がメトキシであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＩＩｂ）：

で表される基を形成する場合、
Ｒ ¹ もＲ ² も２−（Ｎ，Ｎ−ジエチルアミノ）エチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶａ）：

で表される基を形成する場合、
Ｒ ⁷ が、３−（Ｎ−モルホリニル）プロピル、ベンジル、１−エチル−ピロリジン−３−イル、１−メチル−ピペリジン−４−イル、２−（１−メチル−ピロリジン−２−イル）エチル、または３−（Ｎ，Ｎ−ジエチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｂ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−メトキシエチルまたはベンジルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｃ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（Ｎ，Ｎ−ジエチルアミノ）エチルまたは３−（Ｎ，Ｎ−ジメチルアミノ）プロピルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｄ）：

で表される基を形成する場合、
Ｒ ⁷ が、２−（ピロリジン−１−イル）エチルまたは２−ヒドロキシエチルでなく；
各Ｒ ⁵ およびＲ ⁶ がクロロであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｅ）または（ＩＶｆ）：

で表される基を形成する場合、
Ｒ ⁷ がベンジルでなく；
Ｒ ⁵ がクロロであり、Ｒ ⁶ がブロモであり、かつＲ ³ およびＲ ⁴ が結合して、式（ＩＶｇ）、（ＩＶｈ）、（ＩＶｉ）、（ＩＶｊ）、または（ＩＶｋ）：

で表される基を形成する場合、
Ｒ ⁷ がメチルでなく；
Ｒ ⁶ がメチルである場合、
各Ｒ ¹ およびＲ ² がＨであり；および
Ｒ ³ がＨであり、かつ各Ｒ ⁵ およびＲ ⁶ がクロロである場合、
Ｒ ⁷ がメチルでない）
で表される化合物、またはその薬学的に許容できる塩。
［実施形態５］
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、１個の窒素、１個の酸素、または１個の硫黄を任意選択的に含む任意選択的に置換される五員または六員環を形成し、ここで、前記窒素が、Ｒ ⁹ で任意選択的に置換され、またはＲ ³ が、Ｈ、ハロゲン、任意選択的に置換されるＣ _1〜3 アシル、任意選択的に置換されるＣ _1〜3 アルキル、または任意選択的に置換されるＣ _1〜3 アルコキシであり、かつＲ ⁴ が、ハロゲン、任意選択的に置換されるＣ _1〜3 アシル、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、任意選択的に置換されるアミノ、任意選択的に置換されるＣ _1〜6 チオアルキル、または任意選択的に置換されるＣ _6〜10 アリールである、実施形態１〜４のいずれかに記載の化合物。
［実施形態６］
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、１個の硫黄を含む任意選択的に置換される五員環を形成する、実施形態１〜５のいずれかに記載の化合物。
［実施形態７］
Ｒ ³ およびＲ ⁴ が結合して、−Ｃ（Ｒ ^13A ）＝Ｃ（Ｒ ^13B ）−Ｓ−基を形成し、ここで、Ｒ ^13A がＨであり、かつＲ ^13B が、任意選択的に置換されるＣ _1〜3 アルキルまたはＨである、実施形態１〜５のいずれかに記載の化合物。
［実施形態８］
Ｒ ^13B が、任意選択的に置換されるＣ _1〜3 アルキルである、実施形態１１に記載の化合物。
［実施形態９］
Ｒ ^13B が、−Ｃ（Ｏ）−Ｒ ^13C であり、ここで、Ｒ ^13C が、任意選択的に置換されるアミノまたは任意選択的に置換されるＣ _1〜3 アルコキシである、実施形態１２に記載の化合物。
［実施形態１０］
Ｒ ³ およびＲ ⁴ が結合して、−Ｃ（Ｒ ^13A ）＝Ｃ（Ｒ ^13B ）−Ｓ−基を形成し、ここで、Ｒ ^13A がＨであり、かつＲ ^13B が、−Ｃ（Ｏ）−Ｒ ^13C 、Ｈ、またはＣ _1〜6 アミノアルキルであり、ここで、Ｒ ^13C が、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルコキシ、任意選択的に置換されるアミノ、または任意選択的に置換されるＣ _2〜9 ヘテロシクリルである、実施形態１〜５のいずれかに記載の化合物。
［実施形態１１］
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、任意選択的に置換される五員環を形成する、実施形態１〜５のいずれかに記載の化合物。
［実施形態１２］
Ｒ ³ およびＲ ⁴ が結合して、−ＣＨ ₂ ＣＨ ₂ ＣＨ ₂ −基を形成する、実施形態１〜５のいずれかに記載の化合物。
［実施形態１３］
Ｒ ³ およびＲ ⁴ が、それぞれが結合される原子と一緒に、結合して、１個の窒素を含む任意選択的に置換される五員環を形成する、実施形態１〜５のいずれかに記載の化合物。
［実施形態１４］
Ｒ ³ およびＲ ⁴ が結合して、−Ｎ（Ｒ ⁹ ）−ＣＨ＝ＣＨ−基を形成する、実施形態１３に記載の化合物。
［実施形態１５］
Ｒ ³ およびＲ ⁴ が結合して、−Ｘ ¹ −Ｘ ² −Ｘ ³ −を形成し、ここで、
Ｘ ¹ が、−Ｓ−、−Ｏ−、−（ＣＲ ¹⁴ Ｒ ¹⁵ ）−、−Ｃ（Ｒ ¹⁶ ）＝、−Ｎ（Ｒ ⁹ ）−、−Ｎ＝、Ｈ、または任意選択的に置換されるＣ _1〜3 アルキルであり；
Ｘ ² が、存在しないか、−（ＣＲ ¹⁷ Ｒ ¹⁸ ） _n −、−Ｓ−、−Ｏ−、−Ｎ＝、−Ｎ（Ｒ ⁹ ）−、−Ｃ（Ｒ ¹⁹ ）＝、＝Ｎ−、＝Ｃ（Ｒ ²⁰ ）−、または＝Ｃ（Ｒ ²¹ ）−Ｃ（Ｒ ²² ）＝であり；
Ｘ ³ が、−（ＣＲ ¹⁴ Ｒ ¹⁵ ）−、−Ｓ−、−Ｏ−、−Ｎ（Ｒ ⁹ ）−、＝Ｎ−、＝Ｃ（Ｒ ²³ ）−、ハロゲン、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜6 チオアルコキシ、任意選択的に置換されるＣ _1〜3 アルコキシ、または任意選択的に置換されるＣ _6〜10 アリールであり；
各Ｒ ¹⁴ およびＲ ¹⁵ が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり、またはＲ ¹⁴ およびＲ ¹⁵ が結合して、＝Ｏまたは＝Ｓを形成し；
各Ｒ ¹⁷ およびＲ ¹⁸ が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり、またはＲ ¹⁷ およびＲ ¹⁸ が結合して、＝Ｏまたは＝Ｓを形成し；
各Ｒ ¹⁶ 、Ｒ ¹⁹ 、Ｒ ²⁰ 、Ｒ ²¹ 、Ｒ ²² 、およびＲ ²³ が、独立して、Ｈ、または任意選択的に置換されるＣ _1〜3 アルキルであり；および
ｎが、１または２である、実施形態１〜５のいずれかに記載の化合物。
［実施形態１６］
Ｒ ⁷ およびＲ ⁸ が、基−Ｙ ¹ −Ｙ ² −を形成し、ここで：
Ｙ ¹ が、−（ＣＲ ²⁶ Ｒ ²⁷ ） _m −または任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、もしくは任意選択的に置換されるＣ _1〜3 アルカリールであり；および
Ｙ ² が、−（ＣＲ ²⁶ Ｒ ²⁷ ）−またはＨであり；ここで、
各Ｒ ²⁶ およびＲ ²⁷ が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり；
ｍが、１または２であり；および
Ｙ ¹ が、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、または任意選択的に置換されるＣ _1〜3 アルカリールである場合、
Ｙ ² がＨであり、かつＹ ¹ が、Ｙ ² に直接結合されない、実施形態１〜１５のいずれかに記載の化合物。
［実施形態１７］
Ｚ ¹ およびＲ ⁸ が結合して、−Ｚ ³ −Ｙ ¹ −Ｙ ² −を形成し、ここで、
Ｚ ³ が、−Ｏ−、−Ｎ（Ｒ ¹⁰ ）−、−Ｎ＝、−Ｓ−、または−（ＣＲ ¹⁴ Ｒ ¹⁵ ）−であり；
Ｙ ¹ が、−Ｏ−、−Ｎ（Ｒ ¹⁰ ）−、−Ｓ−、−（ＣＲ ²⁶ Ｒ ²⁷ ） _m −、−Ｃ（Ｒ ²⁰ ）＝、＝Ｃ（Ｒ ²⁰ ）−、＝Ｃ（Ｒ ²¹ ）−Ｃ（Ｒ ²² ）＝、任意選択的に置換されるＣ _1〜3 アルキル、任意選択的に置換されるＣ _1〜3 アルクヘテロシクリル、任意選択的に置換されるＣ _1〜3 アルクシクロアルキル、または任意選択的に置換されるＣ _1〜3 アルカリールであり；および Ｙ ² が、−Ｏ−、−Ｓ−、−Ｎ（Ｒ ¹⁰ ）−、−（ＣＲ ²⁶ Ｒ ²⁷ ）−、＝Ｃ（Ｒ ²⁰ ）−、＝Ｎ−、またはＨであり；
ここで、
各Ｒ ²⁰ 、Ｒ ²¹ 、およびＲ ²² が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり；および
各Ｒ ²⁶ およびＲ ²⁷ が、独立して、Ｈまたは任意選択的に置換されるＣ _1〜3 アルキルであり、またはＲ ²⁶ およびＲ ²⁷ が結合して、＝Ｏまたは＝Ｓを形成し；
ｍが、１または２であり；
ここで、Ｙ ² がＨである場合、
原子−Ｚ ³ −Ｙ ¹ −Ｙ ² −の鎖が、２個以下のヘテロ原子を含み、各前記ヘテロ原子が、窒素、酸素、および硫黄から独立して選択される、実施形態１〜５のいずれかに記載の化合物。
［実施形態１８］
化合物：

またはその薬学的に許容できる塩。
［実施形態１９］
式：

で表される、実施形態１８に記載の化合物、またはその薬学的に許容できる塩。
［実施形態２０］

、またはその薬学的に許容できる塩である、実施形態１９に記載の化合物。
［実施形態２１］
実施形態１〜２０のいずれかに記載の化合物、またはその薬学的に許容できる塩と、薬学的に許容できる担体または賦形剤のうちの１つまたは複数とを含む医薬組成物。
［実施形態２２］
経口で、舌下に、口腔に、経皮的に、皮内に、筋肉内に、非経口的に、静脈内に、動脈内に、頭蓋内に、皮下に、眼窩内に、心室内に、髄腔内に、腹腔内に、鼻腔内に、吸入によって、および局所的に投与するために製剤化される、実施形態２１に記載の医薬組成物。
［実施形態２３］
経口投与用に製剤化される、実施形態２２に記載の医薬組成物。
［実施形態２４］
熱ショックタンパク質９０（Ｈｓｐ９０）の作用によって引き起こされる哺乳動物の疾患を治療する方法であって、有効量の、実施形態１〜２０のいずれかに記載の化合物もしくはその薬学的に許容できる塩または実施形態２１に記載の医薬組成物を前記哺乳動物に投与する工程を含む方法。
［実施形態２５］
前記疾患が神経変性疾患である、実施形態２５に記載の方法。
［実施形態２６］
前記神経変性疾患がタウオパチーである、実施形態２５に記載の方法。
［実施形態２７］
前記神経変性疾患が、アルツハイマー病、ハンチントン病、進行性核上まひ、パーキンソン病、ピック病、大脳皮質基底核変性症、慢性外傷性脳症、外傷性脳損傷、または前頭側頭認知症である、実施形態２４または２５に記載の方法。
［実施形態２８］
前記神経変性疾患がアルツハイマー病である、実施形態２７に記載の方法。
［実施形態２９］
前記疾患が増殖性疾患である、実施形態２４に記載の方法。
［実施形態３０］
前記増殖性疾患が癌である、実施形態２９に記載の方法。
［実施形態３１］
哺乳動物の感染症を治療する方法であって、有効量の、実施形態１〜２０のいずれかに記載の化合物またはその薬学的に許容できる塩もしくは実施形態２１に記載の医薬組成物を前記哺乳動物に投与する工程を含む方法。
［実施形態３２］
前記感染症がウイルス感染症である、実施形態３１に記載の方法。
［実施形態３３］
前記ウイルス感染症が、ヘルペスウイルス科（Ｈｅｒｐｅｓｖｉｒｉｄａｅ）、ポリオーマウイルス科（Ｐｏｌｙｏｍａｖｉｒｉｄａｅ）、ポックスウイルス科（Ｐｏｘｖｉｒｉｄａｅ）、レオウイルス科（Ｒｅｏｖｉｒｉｄａｅ）、ビルナウイルス科（Ｂｉｒｎａｖｉｒｉｄａｅ）、ピコルナウイルス科（Ｐｉｃｏｒｎａｖｉｒｉｄａｅ）、フラビウイルス科（Ｆｌａｖｉｖｉｒｉｄａｅ）、アレナウイルス科（Ａｒｅｎａｖｉｒｉｄａｅ）、ヘペウイルス科（Ｈｅｐｅｖｉｒｉｄａｅ）、ラブドウイルス科（Ｒｈａｂｄｏｖｉｒｉｄａｅ）、パラミクソウイルス科（Ｐａｒａｍｏｘｙｖｉｒｉｄａｅ）、ブニヤウイルス科（Ｂｕｎｙａｖｉｒｉｄａｅ）、オルトミクソウイルス科（Ｏｒｔｈｏｍｏｘｙｖｉｒｉｄａｅ）、フィロウイルス科（Ｆｉｌｏｖｉｒｉｄａｅ）、レトロウイルス科（Ｒｅｔｒｏｖｉｒｉｄａｅ）、およびヘパドナウイルス科（Ｈｅｐａｄｎａｖｉｒｉｄａｅ）からなる群から選択される科のウイルスによる感染症である、実施形態３２に記載の方法。
［実施形態３４］
前記感染症が真菌感染症である、実施形態３１に記載の方法。
［実施形態３５］
前記感染症が細菌感染症である、実施形態３１に記載の方法。
［実施形態３６］
前記疾患が、炎症性または自己免疫疾患である、実施形態２４に記載の方法。
［実施形態３７］
前記炎症性または自己免疫疾患が、関節リウマチ、全身性エリテマトーデス、または喘息である、実施形態３６に記載の方法。
［実施形態３８］
前記疾患が心血管疾患である、実施形態２４に記載の方法。
［実施形態３９］
前記心血管疾患が、アテローム性動脈硬化症である、実施形態３８に記載の方法。
［実施形態４０］
前記疾患がアレルギーである、実施形態２４に記載の方法。
［実施形態４１］
前記化合物が、経口で、舌下に、口腔に、経皮的に、皮内に、筋肉内に、非経口的に、静脈内に、動脈内に、頭蓋内に、皮下に、眼窩内に、心室内に、髄腔内に、腹腔内に、鼻腔内に、吸入によって、および局所的に投与される、実施形態２４〜４０のいずれかに記載の方法。
［実施形態４２］
前記化合物が、経口で投与される、実施形態４１に記載の方法。
［実施形態４３］
前記哺乳動物がヒトである、実施形態２４〜４２のいずれかに記載の方法。
［実施形態４４］
Ｈｓｐ９０を阻害する方法であって、細胞を、実施形態１〜２０のいずれかに記載の化合物またはその薬学的に許容できる塩と接触させる工程を含む方法。
［実施形態４５］
前記細胞がインビトロである、実施形態４４に記載の方法。
［実施形態４６］
（ｉ）実施形態２１〜２３のいずれかに記載の医薬組成物と；
（ｉｉ）Ｈｓｐ９０の作用によって引き起こされる哺乳動物の疾患を治療するための（ｉ）の前記医薬組成物の使用説明書と
を含むキット。




Other embodiments are described in the claims.
Examples of embodiments of the present invention include the following.
[Embodiment 1]
Equation (I):

(During the ceremony,
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ;
Z ² is -C (R ³ ) = or -N =;
Each R ¹ and R ² are independently H, optionally substituted C _1-3 acyls, or optionally substituted C _1-3 alkyl;
R ³ and R ⁴ are optionally bonded together with the atoms to which they are bonded, optionally containing 1-3 heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen. Forming a five- or six-membered ring substituted with, where the nitrogen is optionally substituted with R ⁹ , or R ³ is optionally substituted with H, halogen, cyano, C. _{1 to 6} alkyl, C _{1 to 3} alkoxy optionally substituted , or amino optionally substituted, and R ⁴ is halogen, cyano, optionally substituted C _{1 to 6} Alkoxy, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkoxy, or optionally substituted C _6-10 It is aryl;
R ⁵ is halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁶ is a halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five-membered, six-membered, or seven-membered ring; or R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkylcycloalkyl, optionally Selectively substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkaline, and R ⁸ is H;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted ;
R ¹⁰ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or optionally substituted C _1-3 alkalil, and R ¹¹ is H, optionally substituted C _1-3 alkyl, or R ¹⁰ and R ¹¹ are attached. To form = O or = S;
R ^m is H, halogen, cyano, optionally substituted C _1-4 acyl, optionally substituted C _1-4 alkyl, or optionally substituted C _1-3 alkoxy. Yes;
here,
When Z ² is CR ³ , each of R ¹ and R ² is H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro. ,
Z ¹ is not methoxy;
If Z ² is N, R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is the substituted C _1-6 thioalkoxy.
Z ¹ is not cyanomethoxy or aminomethoxy;
If Z ² is CR ³ , R ⁵ and R ⁶ are each chloro, R ³ is H, and R ⁴ is halogen.
Z ¹ is not 2-amino-2-oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy;
Formula (IIa): R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine. When forming a group represented by the formula (IIa),
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl,
When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
Formula (IIIa), where R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVb) :.

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to formulate (IVg), (IVh), (IVi), (IVj). , Or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
Each R ¹ and R ² is H; and
If R ³ is H, Z ¹ is -OR ⁷ , and each R ⁵ and R ⁶ is chloro.
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.
[Embodiment 2]
The compound according to embodiment 1, wherein R ^m is H.
[Embodiment 3]
Equation (Ia):

(During the ceremony,
Each R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally ;
Optional, where R ³ and R ⁴ are bonded together with the atoms to which they are bonded, optionally containing 1-3 heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen. Forming a five- or six-membered ring substituted with, where the nitrogen is optionally substituted with R ⁹ , or R ³ is optionally substituted with H, halogen, cyano, C. _{1 to 6} alkyl, C _{1 to 3} alkoxy optionally substituted , or amino optionally substituted, and R ⁴ is halogen, cyano, optionally substituted C _{1 to 6} Alkoxy, optionally substituted C _1-3 alkoxy, optionally substituted amino, optionally substituted C _1-6 thioalkyl, or optionally substituted C _6-10 aryl Is;
R ⁵ is halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁶ is a halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁷ and R ⁸ bond together with the atoms to which they are bound, optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. Form a five-membered, six-membered, or seven-membered ring; or R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkylcycloalkyl, optionally Selectively substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkaline, and R ⁸ is H;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted ;
Z ¹ is -OR ⁷ , -N (R ¹⁰ ) R ⁷ , -SR ⁷ , or -C (R ¹⁰ ) (R ¹¹ ) R ⁷ ; and
R ¹⁰ is H, C _1-3 acyls optionally substituted, C _1-3 alkyls optionally substituted, C _3-8 cycloalkyls optionally substituted , optionally C _6-10 aryl substituted, C _2-9 heteroaryl optionally substituted, C _2-9 heterocyclyl optionally substituted, C _1-3 arccycloalkyl optionally substituted a C _{1 to 3} alkheterocyclyl or C _{1 to 3} alkaryl being optionally substituted, are optionally substituted, and C _{1 to 3} R ¹¹ is, for H, is optionally substituted It is alkyl, or R ¹⁰ and R ¹¹ combine to form = O or = S;
here,
If R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro.
Z ¹ is not methoxy;
If each of R ⁵ and R ⁶ is chloro, R ³ is H, and R ⁴ is halogen, then
Z ¹ is not 2-amino-2-oxoethoxy, 2- (N, N-diethylamino) ethoxy, methoxy, or benzyloxy;
Formula (IIa): R ⁵ is chloro, R ⁶ is bromo, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ , R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine. When forming a group represented by the formula (IIa),
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl,
When R ⁵ is methoxy, R ⁶ is methyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
Formula (IIIa), where R ⁷ is methyl, R ⁵ is chloro, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined.

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, Z ¹ is −OR ⁷ , and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVb) :.

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, Z ¹ is −OR ⁷ and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, Z ¹ is -OR ⁷ , and R ³ and R ⁴ are combined to formulate (IVg), (IVh), (IVi), (IVj). , Or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
Each R ¹ and R ² is H; and
If R ³ is H, Z ¹ is -OR ⁷ , and each R ⁵ and R ⁶ is chloro.
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.
[Embodiment 4]
Equation (Ib):

(During the ceremony,
Each of R ¹ and R ² is a C _1-3 alkyl that is independently substituted with H or optionally ;
Five of which R ³ and R ⁴ are optionally bonded together with the atoms to which they are bonded, optionally containing one nitrogen, one sulfur, or one oxygen. A C _1-6 alkyl, which forms a member or six-membered ring, wherein the nitrogen is optionally substituted with R ⁹ , or R ³ is optionally substituted with H, halogen, cyano , Optionally substituted C _1-3 alkoxy, or optionally substituted amino, and R ⁴ is halogen, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _1-3 alkoxy substituted with, amino optionally substituted, C _1-6 thioalkoxy optionally substituted, or C _6-10 aryl optionally substituted ;
R ⁵ is halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁶ is a halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁷ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 arccycloalkyl, optionally substituted C _1-3 archeterocyclyl, or optionally substituted C _1-3 alkaline to be substituted with , and R ⁸ is H; or R ⁷ and R ⁸ are bonded together with the atom to which each is attached and optionally substituted. Form a five-, six-, or seven-membered ring; and
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil that is optionally substituted ;
here,
If R ¹ and R ² are each H, R ³ is H, R ⁴ is methyl or chloro, and R ⁵ and R ⁶ are each chloro.
R ⁷ is not methyl;
If each of R ⁵ and R ⁶ is chloro, R ³ is H, and R ⁴ is halogen, then
R ⁷ is not 2-amino-2-oxoethyl, 2- (N, N-diethylamino) ethyl, methyl, or benzyl;
R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are combined, formula (IIa):

When forming a group represented by
R ⁷ is methyl, ethyl, n-propyl, 2- (N-pyrazolyl) ethyl, 2- (N-imidazolyl) ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo- Not propyl, 2- (N, N-dimethylamino) -ethyl, difluoromethyl, or 2- (t-butylamino) ethyl;
When each R ⁵ and R ⁶ is bromo and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
When each R ⁵ and R ⁶ is chloro, R ⁸ is H, and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is methyl, 2- (N-imidazolyl) ethyl, methoxymethyl, 2- (N-pyrazolyl) ethyl, 2- (3-methylpyrazol-1-yl) ethyl, 2-pyridyl-methyl, 1,3 -Dimethyl-1H-1,2,4-triazole-5-yl-methyl, 2-pyrimidinylmethyl, imidazole-2-yl-methyl, 5-methyl-isoxazole-3-yl-methyl, 4-methyl-imidazole Not -5-yl-methyl or 3-methyl-1,2,4-oxadiazol-5-yl-methyl;
Each R ⁵ and R ⁶ is chloro, R ⁷ and R ⁸ combine to form −CH ₂ −CH ₂ −, and R ³ and R ⁴ combine to represent formula (IIa). When forming a group
R ⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl;
When R ⁵ is methoxy, R ⁶ is methyl, and R ³ and R ⁴ are combined to form a group represented by the formula (IIa).
R ⁷ is not methyl;
When R ⁵ is chloro, R ⁶ is ethyl, and R ³ and R ⁴ combine to form a group represented by formula (IIa).
R ⁷ is not methyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are bound to formula (IIb) or (IIc).

When forming a group represented by
R ⁷ is not methyl or 2- (N, N-diethylamino) ethyl;
R ⁷ is methyl, R ⁵ is chloro, and R ³ and R ⁴ are combined, formula (IIIa).

When forming a group represented by
R ⁶ is not bromo;
R ⁵ is chloro, R ⁶ is methoxy, and R ³ and R ⁴ are combined, formula (IIIb):

When forming a group represented by
Neither R ¹ nor R ² is 2- (N, N-diethylamino) ethyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVa):

When forming a group represented by
R ⁷ is 3- (N-morpholinyl) propyl, benzyl, 1-ethyl-pyrrolidin-3-yl, 1-methyl-piperidin-4-yl, 2- (1-methyl-pyrrolidin-2-yl) ethyl, Or not 3- (N, N-diethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVb):

When forming a group represented by
R ⁷ is not 2-methoxyethyl or benzyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVc):

When forming a group represented by
R ⁷ is not 2- (N, N-diethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined, formula (IVd):

When forming a group represented by
R ⁷ is not 2- (pyrrolidin-1-yl) ethyl or 2-hydroxyethyl;
Each R ⁵ and R ⁶ is chloro, and R ³ and R ⁴ are combined to form formula (IVe) or (IVf):

When forming a group represented by
R ⁷ is not benzyl;
R ⁵ is chloro, R ⁶ is bromo, and R ³ and R ⁴ are bound to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

When forming a group represented by
R ⁷ is not methyl;
If R ⁶ is methyl
Each R ¹ and R ² is H; and
If R ³ is H and each R ⁵ and R ⁶ is chloro
R ⁷ is not methyl)
A compound represented by, or a pharmaceutically acceptable salt thereof.
[Embodiment 5]
R ³ and R ⁴ are optionally substituted together with the atoms to which they are attached, optionally containing one nitrogen, one oxygen, or one sulfur. Forming a member or six-membered ring, where the nitrogen is optionally substituted with R ⁹ , or R ³ is optionally substituted with H, halogen, C _1-3 acyl, optionally. C _1-3 alkyl optionally substituted, or C _1-3 alkoxy optionally substituted , and R ⁴ is halogen, C _1-3 acyl optionally substituted, optionally substituted C _1-3 alkyl substituted with, C _1-3 alkoxy optionally substituted, amino optionally substituted, C _1-6 thioalkyl optionally substituted , or optionally substituted The compound according to any of embodiments 1 to 4, wherein the C _{6 to 10} aryl is substituted .
[Embodiment 6]
In any of embodiments 1-5, where R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one sulfur. The compound described.
[Embodiment 7]
R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is optionally substituted. The compound according to any of embodiments 1-5, which is C _1-3 alkyl or H.
[Embodiment 8]
The compound according to embodiment 11, wherein R ^13B is a C _1-3 alkyl optionally substituted .
[Embodiment 9]
In Embodiment 12, R ^13B is −C (O) −R ^13C , where R ^13C is an optionally substituted amino or an optionally substituted C _1-3 alkoxy. The compound described.
[Embodiment 10]
R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is -C (O). -R ^13C , H, or C _1-6 aminoalkyl, where R ^13C is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optional. The compound according to any of embodiments 1-5, which is an amino that is selectively substituted, or a C _2-9 heterocyclyl that is optionally substituted .
[Embodiment 11]
The compound according to any one of embodiments 1-5, wherein R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form a five-membered ring that is optionally substituted.
[Embodiment 12]
The compound according to any one of embodiments 1 to 5, wherein R ³ and R ⁴ bind to form a −CH ₂ CH ₂ CH ₂ − group.
[Embodiment 13]
In any of embodiments 1-5, where R ³ and R ⁴ are bonded together with the atoms to which they are bonded to form an optionally substituted five-membered ring containing one nitrogen. The compound described.
[Embodiment 14]
13. The compound of embodiment 13, wherein R ³ and R ⁴ combine to form the -N (R ⁹ ) -CH = CH- group.
[Embodiment 15]
R ³ and R ⁴ combine to form −X ¹ −X ² −X ³⁻ , where
X ¹ is replaced with -S-, -O-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, -N (R ⁹ )-, -N =, H, or optionally. C _1-3 alkyl;
X ² does not exist, or-(CR ¹⁷ R ¹⁸ ) _n-, -S-, -O- , -N =, -N (R ⁹ )-, -C (R ¹⁹ ) =, = N-, = C (R ²⁰ )-or = C (R ²¹ ) -C (R ²² ) =;
X ³ is optionally replaced with − (CR ¹⁴ R ¹⁵ ) −, −S−, −O−, −N (R ⁹ ) −, = N−, = C (R ²³ ) −, halogen. C _1-3 alkyl, optionally substituted C _1-6 thioalkoxy, optionally substituted C _1-3 alkoxy, or optionally substituted C _6-10 aryl;
Each R ¹⁴ and R ¹⁵ is an independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form = O or = S;
Each R ¹⁷ and R ¹⁸ are independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form = O or = S;
Each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , and R ²³ are H, or C _1-3 alkyl optionally substituted ; and
The compound according to any one of embodiments 1 to 5, wherein n is 1 or 2.
[Embodiment 16]
R ⁷ and R ⁸ form the group −Y ¹ −Y ² −, where:
Y ¹ is − (CR ²⁶ R ²⁷ ) _m − or optionally substituted C _1-3 alkyl, optionally substituted C _1-3 archeterocyclyl, optionally substituted C _{1 ~ 3} arccycloalkyl, or C _1-3 alkaline , optionally substituted ; and
Y ² is-(CR ²⁶ R ²⁷ )-or H; where
Each R ²⁶ and R ²⁷ is a C _1-3 alkyl that is independently substituted with H or optionally ;
m is 1 or 2; and
Y ¹ is optionally substituted C _1-3 alkyl, optionally substituted C _1-3 archeterocyclyl, optionally substituted C _1-3 arccycloalkyl, or optionally substituted If C _1-3 alkaline is replaced by
The compound according to any one of embodiments 1 to 15 , wherein Y ² is H and Y ¹ is not directly bound to Y ² .
[Embodiment 17]
Z ¹ and R ⁸ combine to form −Z ³ −Y ¹ −Y ² −, where
Z ³ is -O-, -N (R ¹⁰ )-, -N =, -S-, or-(CR ¹⁴ R ¹⁵ )-;
Y ¹ is -O-, -N (R ¹⁰ )-, -S-,-(CR ²⁶ R ²⁷ ) _m- , -C (R ²⁰ ) =, = C (R ²⁰ )-, = C (R) ^{21) -C (R 22) =} , C 1~3 alkyl, C _{1 to 3} alkheterocyclyl, C _{1 to 3} alkcycloalkyl which is optionally substituted is optionally substituted is optionally substituted Alkyl, or C _1-3 alkaline alcohol optionally substituted ; and Y ² are -O-, -S-, -N (R ¹⁰ )-,-(CR ²⁶ R ²⁷ )-, = C (R ²⁰ )-, = N-, or H;
here,
Each R ²⁰ , R ²¹ , and R ²² are C _1-3 alkyl independently substituted with H or optionally ; and
Each R ²⁶ and R ²⁷ is an independently H or optionally substituted C _1-3 alkyl, or R ²⁶ and R ²⁷ combine to form = O or = S;
m is 1 or 2;
Here, if Y ² is H,
The ^{first to} fifth embodiments, wherein the chain of atoms −Z ³ −Y ¹ −Y ² − contains no more than two heteroatoms, and each heteroatom is selected independently of nitrogen, oxygen, and sulfur. The compound according to any.
[Embodiment 18]
Compound:

Or its pharmaceutically acceptable salt.
[Embodiment 19]
formula:

The compound according to embodiment 18, or a pharmaceutically acceptable salt thereof, represented by.
[Embodiment 20]

, Or a pharmaceutically acceptable salt thereof, according to embodiment 19.
[Embodiment 21]
A pharmaceutical composition comprising the compound according to any of embodiments 1-20, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier or excipient.
[Embodiment 22]
Orally, sublingually, orally, percutaneously, intradermally, intramuscularly, parenterally, intravenously, intraarterial, intracranial, subcutaneously, intraorbitally, intraventricularly The pharmaceutical composition according to embodiment 21, which is formulated for intramedullary, intraperitoneal, intranasal, inhalation, and topical administration.
[Embodiment 23]
The pharmaceutical composition according to embodiment 22, which is formulated for oral administration.
[Embodiment 24]
A method of treating a mammalian disease caused by the action of heat shock protein 90 (Hsp90), wherein an effective amount of the compound according to any of embodiments 1-20 or a pharmaceutically acceptable salt thereof or an embodiment thereof. A method comprising the step of administering the pharmaceutical composition according to form 21 to the mammal.
[Embodiment 25]
25. The method of embodiment 25, wherein the disease is a neurodegenerative disease.
[Embodiment 26]
25. The method of embodiment 25, wherein the neurodegenerative disease is tauopathy.
[Embodiment 27]
The neurodegenerative disease is Alzheimer's disease, Huntington's disease, progressive supraclavicular paralysis, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia. The method according to embodiment 24 or 25.
[Embodiment 28]
27. The method of embodiment 27, wherein the neurodegenerative disease is Alzheimer's disease.
[Embodiment 29]
24. The method of embodiment 24, wherein the disease is a proliferative disease.
[Embodiment 30]
29. The method of embodiment 29, wherein the proliferative disease is cancer.
[Embodiment 31]
A method of treating an infectious disease in a mammal, wherein an effective amount of the compound according to any one of embodiments 1 to 20 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to embodiment 21 is administered. A method comprising the step of administering to an animal.
[Embodiment 32]
31. The method of embodiment 31, wherein the infectious disease is a viral infectious disease.
[Embodiment 33]
The viral infectious diseases include Herpesvirusidae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornavirus. , Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramixyviridae, Paramoxyviridae, Buniaviridae, Buniaviridae The method according to embodiment 32, which is an infection caused by a virus of a family selected from the group consisting of the family Flaviviridae, the family Retrovirus, and the family Hepadnaviridae.
[Embodiment 34]
31. The method of embodiment 31, wherein the infectious disease is a fungal infection.
[Embodiment 35]
31. The method of embodiment 31, wherein the infectious disease is a bacterial infection.
[Embodiment 36]
24. The method of embodiment 24, wherein the disease is an inflammatory or autoimmune disease.
[Embodiment 37]
36. The method of embodiment 36, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma.
[Embodiment 38]
24. The method of embodiment 24, wherein the disease is a cardiovascular disease.
[Embodiment 39]
38. The method of embodiment 38, wherein the cardiovascular disease is atherosclerosis.
[Embodiment 40]
24. The method of embodiment 24, wherein the disease is allergic.
[Embodiment 41]
The compound is orally, sublingually, orally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intraarterially, intracranial, subcutaneously, intraorbitally. The method according to any of embodiments 24-40, which is administered intraventricularly, intrathecally, intraperitoneally, intranasally, by inhalation, and topically.
[Embodiment 42]
41. The method of embodiment 41, wherein the compound is administered orally.
[Embodiment 43]
The method according to any of embodiments 24-42, wherein the mammal is a human.
[Embodiment 44]
A method of inhibiting Hsp90, comprising contacting the cells with the compound according to any of embodiments 1-20 or a pharmaceutically acceptable salt thereof.
[Embodiment 45]
44. The method of embodiment 44, wherein the cells are in vitro.
[Embodiment 46]
(I) With the pharmaceutical composition according to any of embodiments 21-23;
(Ii) With the instructions for use of the pharmaceutical composition of (i) for treating a mammalian disease caused by the action of Hsp90.
Kit including.

Claims (20)

Equation (I):

(During the ceremony,
Z ¹ is -OR ⁷ or -SR ⁷ ;
Z ² is -C (R ³ ) =;
Each R ¹ and R ² are independently H, optionally substituted C _1-3 acyls, or optionally substituted C _1-3 alkyl;
R ³ and R ⁴ combine to form −X ¹ −X ² −X ³ −; or R ³ is H, halogen, cyano , optionally substituted C _1-3 acyl , optional C _{1 to 6} alkyl optionally substituted, C _1-3 alkoxy optionally substituted, or amino optionally substituted, and R ⁴ is halogen, cyano , optionally substituted. C _1-3 acyls that are optionally substituted, C _1-6 alkyls that are optionally substituted, C _1-3 alkoxys that are optionally substituted, amino that is optionally substituted, or optionally substituted. C _{1 to 6} thioalkoxy, where
X ¹ is -S-, -O-,-(CR ¹⁴ R ¹⁵ )-, -C (R ¹⁶ ) =, -N (R ⁹ )-, or -N =;
X ² is − (CR ¹⁷ R ¹⁸ ) _n − , −C (R ¹⁹ ) =, = C (R ²⁰ ) −, or = C (R ²¹ ) −C (R ²² ) =;
X ³ is-(CR ¹⁴ R ¹⁵ )-, -S-, -O-, -N (R ⁹ )-, = N-, or = C (R ²³ )-;
Each R ¹⁴ and R ¹⁵ is an independently H or optionally substituted C _1-3 alkyl, or R ¹⁴ and R ¹⁵ combine to form = O or = S;
Each R ¹⁷ and R ¹⁸ are independently H or optionally substituted C _1-3 alkyl, or R ¹⁷ and R ¹⁸ combine to form = O or = S;
Each R ¹⁶ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are C _1-3 alkyls that are independently substituted with H, or optionally; and n is 1 or 2. Is;
R ⁵ is halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁶ is a halogen, H, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, or CN;
R ⁷ and R ⁸ together with the atoms to which each is bonded, bonded to, a saturated five-membered ring to form is arbitrary optionally substituted;
R ⁹ is H, optionally substituted C _1-3 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 to 9} substituted heteroaryl, C _{2 to 9} heterocyclyl are optionally substituted, C _{1 to 3} alkcycloalkyl which is optionally substituted, C _{1 to 3} alk is optionally substituted Heterocyclyl, or C _1-3 alkalil optionally substituted; and R ^m is H, halogen, cyano, optionally substituted C _1-4 acyl, optionally substituted. C _{1 to 4} alkyl or Ru Oh optionally substituted by C _{1 to 3} alkoxy)
A compound represented by, or a pharmaceutically acceptable salt thereof. Equation (Ia):

The compound according to claim 1, which is a compound represented by the above, or a pharmaceutically acceptable salt thereof. Equation (Ib):

The compound according to claim 1, which is a compound represented by the above, or a pharmaceutically acceptable salt thereof. R ³ is H, halogen, optionally substituted C _1-3 acyl, optionally substituted C _1-3 alkyl, or optionally substituted C _1-3 alkoxy. And R ⁴ is halogen, optionally substituted C _1-3 acyl, optionally substituted C _1-3 alkyl, optionally substituted C _1-3 alkoxy, optionally substituted Amino to be substituted, or C _1-6 thioalkoxy to be optionally substituted;
R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H and R ^13B is optionally substituted. Is C _1-3 alkyl or H; R ³ and R ⁴ combine to form the -C (R ^13A ) = C (R ^13B ) -S- group, where R ^13A is H. ^Yes , and R ^13B is -C (O) -R ^13C , H, or C _1-6 aminoalkyl, where R ^13C is optionally substituted C _1-3 alkyl, optionally. C _1-3 alkoxy, which is optionally substituted, amino, which is optionally substituted, or C _2-9 heterocyclyl, which is optionally substituted;
R ³ and R ⁴ combine to form the -CH ₂ CH ₂ CH ₂ − group; or R ³ and R ⁴ combine to form the -N (R ⁹ ) -CH = CH- group. The compound according to any one of claims 1 to 3. R ^13B is an optionally substituted C _1-3 alkyl or C (O) -R ^13C , where R ^13C is optionally substituted amino or optionally substituted. The compound according to claim 4, which is a C _1-3 alkoxy substituted with. R ⁷ and R ⁸ form the group −Y ¹ −Y ² −, where:
Y ¹ is-(CR ²⁶ R ²⁷ ) _m- ; and Y ² is-(CR ²⁶ R ²⁷ )-where;
Each R ²⁶ and R ²⁷ is a C _1-3 alkyl that is independently substituted with H or optionally;
The compound according to any one of claims 1 to 3, wherein m is 1. Z ¹ and R ⁸ combine to form −Z ³ −Y ¹ −Y ² −, where
Z ³ is a -O-;
Y ^{1 is, - (CR 26 R 27)} m - a is; and Y ^{2, - (CR 26 R 27)} - a and;
here,
Each R ²⁶ and R ²⁷ are independently H or optionally substituted C _1-3 alkyl, or R ²⁶ and R ²⁷ combine to form = O or = S; and The compound according to claim 1 or 2 , wherein m is 1. Less than:

A compound selected from the group consisting of and its pharmaceutically acceptable salts. Less than:

A compound selected from the group consisting of and its pharmaceutically acceptable salts. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier or excipient. Orally, sublingually, orally, percutaneously, intradermally, intramuscularly, parenterally, intravenously, intraarterial, intracranial, subcutaneously, intraorbitally, intraventricularly The pharmaceutical composition according to claim 10, which is formulated for intramedullary, intraperitoneal, intranasal, inhalation, or topical administration. The pharmaceutical composition according to claim 10 or 11, for use in the treatment of a mammalian disease, wherein the disease is a neurodegenerative disease, a proliferative disease, an inflammatory or autoimmune disease, a cardiovascular disease or an allergy. The above-mentioned pharmaceutical composition. The diseases are tauopathy, Alzheimer's disease, Huntington's disease, progressive nuclear paralysis, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, frontotemporal dementia, cancer, joints. The pharmaceutical composition according to claim 12, which is rheumatism, systemic erythematosus, asthma, or atherosclerosis. The pharmaceutical composition according to claim 12 or 13, wherein the mammal is a human. The pharmaceutical composition according to claim 10 or 11, for use in the treatment of mammalian infectious diseases. The pharmaceutical composition according to claim 15, wherein the infectious disease is a viral infection, a fungal infection or a bacterial infection. The viral infectious diseases include Herpesvirusidae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornavirus. , Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramixyviridae, Paramoxyviridae, Buniaviridae, Buniaviridae The pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical composition is an infection caused by a virus of a family selected from the group consisting of the family Flaviviridae, the family Retrovirus, and the family Hepadnaviridae. The pharmaceutical composition according to any one of claims 15 to 17, wherein the mammal is a human. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for inhibiting Hsp90 in cells. (I) With the pharmaceutical composition according to claim 10 or 11.
(Ii) With instructions for use of the pharmaceutical composition of (i) for treating a disease selected from the group consisting of neurodegenerative diseases, proliferative diseases, inflammatory or autoimmune diseases, cardiovascular diseases, or allergies. Kit including.

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